Publications by authors named "Xiuwei Yang"

81 Publications

Downregulation of GTSE1 leads to the inhibition of proliferation, migration, and Warburg effect in cervical cancer by blocking LHDA expression.

J Obstet Gynaecol Res 2021 Sep 5. Epub 2021 Sep 5.

Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.

Aim: G2 and S phase-expressed-1 (GTSE1) has been identified to play a vital role in several kinds of cancers, but its role in cervical cancer development remains unknown. Herein, we aimed to reveal the role and underlying mechanism of GTSE1 in cervical cancer cell growth, migration, and aerobic glycolysis.

Methods: GTSE1 expression levels in cervical cancer tissues and normal cervical tissues were determined by real time PCR and immunohistochemistry. Human short hairpin RNA was used to downregulate GTSE1 level in cervical cancer cells SiHa and HeLa cells. Colony formation, cell counting kit-8, and wound-healing assays were used for cell function evaluation. Lactate production, lactate dehydrogenase activity, and glucose concentration were tested to assess the Warburg effect.

Results: GTSE1 expressions at both mRNA and protein levels were significantly elevated in cervical cancer tissues compared with normal tissues. Downregulation of GTSE1 induced significant repressions in cell colony formation, viability and migration, and Warburg effect, as well as reduced expression of lactate dehydrogenase isoform A (LDHA) at mRNA and protein levels. Additionally, downregulation of GTSE1 weakened the tumorigenesis of HeLa and SiHa cells in vivo.

Conclusion: This study demonstrated that downregulation of GTSE1 led to significant inhibitions in cell proliferation, migration, tumorigenesis, and Warburg effect in cervical cancer by blocking the expression of LHDA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jog.15000DOI Listing
September 2021

HIST2H2BF Potentiates the Propagation of Cancer Stem Cells Notch Signaling to Promote Malignancy and Liver Metastasis in Colorectal Carcinoma.

Front Oncol 2021 12;11:677646. Epub 2021 Aug 12.

Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Background: Growing evidence demonstrates that the initiation and progression of colorectal carcinoma (CRC) is related to the presence of cancer stem cells (CSCs). However, the mechanism through which the stem cell features of CRC cells are maintained is poorly understood. In this study, we identified the oncogenic histone cluster 2 H2B family member F (HIST2H2BF) and aimed to investigate the function of upregulated HIST2H2BF expression in maintaining the stem cell features of CRC cells, which accelerate the progression of CRC.

Methods: HIST2H2BF expression was quantified using real-time polymerase chain reaction, immunohistochemistry, and western blotting. The correlation between CpG island methylation status and HIST2H2BF re-expression was assessed through bisulfite sequencing polymerase chain reaction, methylation-specific polymerase chain reaction, and 5-Aza-dC treatment. Functional assays were performed on CRC cells and mice to investigate the HIST2H2BF-induced stem cell-like and cancer properties of CRC. Using the Notch pathway inhibitor FLI-06, the regulatory effect of HIST2H2BF on downstream Notch signaling was confirmed.

Results: HIST2H2BF was highly expressed in CRC tissues and cell lines. The reactivation of HIST2H2BF in CRC stems at least in part from the hypomethylated CpG islands. CRC patients with high HIST2H2BF expression have poor survival outcomes. Functional studies have shown that HIST2H2BF promotes CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. Blockage of the Notch pathway reduced the stem cell-like and cancer properties.

Conclusion: Our study suggests that HIST2H2BF upregulation enhances the CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. These results identified a new perspective on the mechanism by which the stem cell features of CRC cells are maintained and highlighted the potential novel therapeutic targets for CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.677646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406628PMC
August 2021

STK39 promotes breast cancer invasion and metastasis by increasing SNAI1 activity upon phosphorylation.

Theranostics 2021 11;11(16):7658-7670. Epub 2021 Jun 11.

Department of Pharmacology & Nutritional Sciences, University of Kentucky, College of Medicine, Lexington, KY 40506, United States.

SNAI1 is widely regarded as a master driver of epithelial-mesenchymal transition (EMT) and associated with breast cancer progression and metastasis. This pro-malignant role is strongly linked to posttranslational modification, especially phosphorylation, which controls its protein levels and subcellular localization. While multiple kinases are implicated in regulation of SNAI1 stability, the precise mechanism by which SNAI1 is stabilized in tumors remains to be fully elucidated. : A series of and experiments were conducted to reveal the regulation of SNAI1 by Serine/Threonine Kinase 39 (STK39) and the role of STK39 in breast cancer metastasis. We identified STK39, a member of Stem 20-like serine/threonine kinase family, as a novel posttranslational regulator that enhances the stability of SNAI1. Inhibition of STK39 via knockdown or use of a specific inhibitor resulted in SNAI1 destabilization. Mechanistically, STK39 interacted with and phosphorylated SNAI1 at T203, which is critical for its nuclear retention. Functionally, STK39 inhibition markedly impaired the EMT phenotype and decreased tumor cell migration, invasion, and metastasis both and . These effects were rescued by ectopic SNAI1 expression. In addition, depletion of STK39 dramatically enhanced sensitivity to chemotherapeutic agents. Our study demonstrated that STK39 is a key mediator of SNAI1 stability and is associated with the pro-metastatic cellular process, highlighting the STK39-SNAI1 signaling axis as promising therapeutic targets for treatments of metastatic breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.62406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315073PMC
August 2021

Computational and experimental characterization of isomers of escin-induced renal cytotoxicity by inhibiting heat shock proteins.

Eur J Pharmacol 2021 Oct 27;908:174372. Epub 2021 Jul 27.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address:

Escin is a natural mixture of triterpene saponins, exhibits anti-oedematous properties and promotes venous drainage by oral administration or injection. Upon clinical application of escin, adverse kidney reactions have been reported and the nephrotoxic mechanism responsible for this reaction remains elusive. In the present study, four isomeric escins (β-form: escin Ia and escin Ib; α-form: isoescin Ia and isoescin Ib) were found severely decreasing the cell viability of human kidney (HK-2) cells. A decline in HK-2 cell viability caused by sodium aescinate (a mixture of four isomers) was reduced after β-glucuronidase hydrolysis. In addition, sodium aescinate concentration-dependently inhibited the expression level of heat shock proteins (HSPs) in the Madin-Darby Canine Kidney (MDCK) cells. Moreover, with molecular docking and molecular dynamics simulation, these four isomeric escins could directly bind to the ATP-binding domain of HSP70 and HSP90, thus competitively inhibiting the function of HSPs. Escin Ia is bound to HSPs with the lowest binding free energy, which is consistent with the observation that escin Ia most severely decreases HK-2 cell viability. Thus, we demonstrate a heretofore unknown molecular mechanism of escin-induced renal cytotoxicity as well as identify HSPs as potential targets for the renal cytotoxic effect of escin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2021.174372DOI Listing
October 2021

Complete chloroplast genome sequence of Herbich.

Mitochondrial DNA B Resour 2021 28;6(8):2117-2119. Epub 2021 Jun 28.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicine, School of Pharmaceutical Science, Peking University, Beijing, China.

Herbich is one of 17 species of in China, and it is often used as an ornamental plant. The chloroplast genome size of Herbich is 150,995 bp, including a large single-copy region (82,771 bp), a small single-copy region (18,308 bp), and a pair of inverted repeats regions (24,958 bp). Total 112 genes were annotated, including 79 protein-coding genes, four ribosomal RNA genes, and 29 transfer RNA genes. The phylogenetic position of Herbich is close to .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/23802359.2021.1942261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245063PMC
June 2021

CD151 drives cancer progression depending on integrin α3β1 through EGFR signaling in non-small cell lung cancer.

J Exp Clin Cancer Res 2021 Jun 9;40(1):192. Epub 2021 Jun 9.

Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.

Background: Tetraspanins CD151, a transmembrane 4 superfamily protein, has been identified participating in the initiation of a variety of cancers. However, the precise function of CD151 in non-small cell lung cancer (NSCLC) remains unclear. Here, we addressed the pro-tumoral role of CD151 in NSCLC by targeting EGFR/ErbB2 which favors tumor proliferation, migration and invasion.

Methods: First, the mRNA expression levels of CD151 in NSCLC tissues and cell lines were measured by RT-PCR. Meanwhile, CD151 and its associated proteins were analyzed by western blotting. The expression levels of CD151 in NSCLC samples and its paired adjacent lung tissues were then verified by Immunohistochemistry. The protein interactions are evaluated by co-immunoprecipitation. Flow cytometry was applied to cell cycle analysis. CCK-8, EdU Incorporation, and clonogenic assays were used to analyze cell viability. Wound healing, transwell migration, and matrigel invasion assays were utilized to assess the motility of tumor cells. To investigate the role of CD151 in vivo, lung carcinoma xenograft mouse model was applied.

Results: High CD151 expression was identified in NSCLC tissues and cell lines, and its high expression was significantly associated with poor prognosis of NSCLC patients. Further, knockdown of CD151 in vitro inhibited tumor proliferation, migration, and invasion. Besides, inoculation of nude mice with CD151-overexpressing tumor cells exhibited substantial tumor proliferation compared to that in control mice which inoculated with vector-transfected tumor cells. Noteworthy, we found that overexpression of CD151 conferred cell migration and invasion by interacting with integrins. We next sought to demonstrate that CD151 regulated downstream signaling pathways via activation of EGFR/ErbB2 in NSCLC cells. Therefore, we infer that CD151 probably affects the sensitivity of NSCLC in response to anti-cancer drugs.

Conclusions: Based on these results, we demonstrated a new mechanism of CD151-mediated tumor progression by targeting EGFR/ErbB2 signaling pathway, by which CD151 promotes NSCLC proliferation, migration, and invasion, which may considered as a potential target of NSCLC treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13046-021-01998-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191020PMC
June 2021

The Context-Dependent Impact of Integrin-Associated CD151 and Other Tetraspanins on Cancer Development and Progression: A Class of Versatile Mediators of Cellular Function and Signaling, Tumorigenesis and Metastasis.

Cancers (Basel) 2021 Apr 21;13(9). Epub 2021 Apr 21.

Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.

As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), and the Wnt/β-catenin pathway, as well as the dynamics of exosome and cellular metabolism. Finally, we discuss the implications of the highly plastic nature and epigenetic susceptibility of CD151 expression, function, and signaling for clinical diagnosis and therapeutic intervention for human cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13092005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122392PMC
April 2021

Identification of Novel Prognostic Risk Signatures of Soft Tissue Sarcoma Based on Ferroptosis-Related Genes.

Front Oncol 2021 6;11:629868. Epub 2021 Apr 6.

Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.

Background: The role of ferroptosis in tumorigenesis has been confirmed in previous studies. However, the comprehensive analysis of ferroptosis-related gene (FRG) to study the role of FRG in soft tissue sarcoma (STS) is lacking.

Methods: RNA sequencing profile of TCGA-SARC cohort and GTEx were used to select differentially expressed FRGs (DEFRGs). Univariate, LASSO, and multivariate Cox analyses were selected to determine overall survival (OS)- and disease-free survival (PFS)-related FRGs. Two prognostic signatures were established and validated in two independent sets from Gene Expression Omnibus (GEO). Finally, the expression of key FRGs were validated with RT-qPCR.

Results: In total, 198 FRGs (90.4%) were abnormally expressed in STS. Twelve DEFRGs were incorporated in the final signatures and showed favorable discrimination in both training and validation cohorts. Patients in the different risk groups not only showed different prognosis, but also showed different infiltration of immune cells. Two nomograms combining signature and clinical variables were established and the C-indexes were 0.852 and 0.752 for the OS and DFS nomograms, respectively. Finally, the expression of NOX5, HELLS, and RPL8 were validated with RT-qPCR.

Conclusion: This comprehensive analysis of the FRG landscape in STS revealed novel FRGs related to carcinogenesis and prognosis. These findings have implications for prognosis and therapeutic responses, which revealed potential prognostic biomarkers and promote precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.629868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056866PMC
April 2021

The complete plastid genome sequence of (L.) Ker Gawl. (Asparagaceae).

Mitochondrial DNA B Resour 2021 Mar 1;6(2):653-655. Epub 2021 Mar 1.

Hainan Provincial Key Laboratory of Resources Conservation and Development of Southern Medicine, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Haikou, China.

is a shrub native to tropical Africa classified in the family Asparagaceae. It is a common horticultural plant grown as a hedge as well as an ornamental house plant for its green leaves, attractive shape and fragrant flowers. The species has been used for many medicinal purposes including inducing labor, treating malnutrition and fighting illness. Here, we investigated the complete plastid genome of using Illumina 150 bp next-generation sequencing technologies. assembly and annotation showed that the chloroplast genome is a typical quadripartite structure with 37.5% GC content. A pair of inverted repeats (IRs, 26,507 bp each) were separated by one large single-copy region (LSC, 83,703 bp) and one small single-copy region (SSC, 18,466 bp). The chloroplast genome is 155,183 bp in length and contained 131 genes of which 12 are intron-containing genes, comprising 85 protein-coding, 38 tRNA, and 8 rRNA genes. Phylogenetic analysis of and 11 plastomes obtained from GenBank shows that it is closely related to .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/23802359.2020.1860719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928031PMC
March 2021

Metabolic Profiling of Nuciferine In Vivo and In Vitro.

J Agric Food Chem 2020 Nov 18. Epub 2020 Nov 18.

State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.

Nuciferine (NF) is one of the main constituents of Lotus () leaves which have been widely used in both food and drug formulations in China. Although possessing a broad spectrum of bioactivities, the metabolic characteristics of NF are inadequately unknown after oral gavage with this NF. The present study was performed to characterize its metabolism in vivo and in vitro. After NF oral gavage with mice, a total of 55 metabolites, containing 14 novel phase I metabolites and 18 novel phase II metabolites, were identified with high-resolution mass spectrometry-based metabolomics. Recombinant enzyme screenings showed that multiple cytochrome P450s, two UDP-glucuronosyltransferases (UGT1A4, UGT1A9), and several sulfotransferases (SULTs) participated in the metabolism of NF. In silico prediction and molecular docking of NF to the polymorphic enzymes (CYPs) provided additional support for the above experiments. This research details metabolic characteristics and provides an important reference basis for further application of NF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jafc.0c04468DOI Listing
November 2020

BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways.

Cell Oncol (Dordr) 2020 Dec 2;43(6):1049-1066. Epub 2020 Oct 2.

Department of Pharmacology and Nutritional Sciences, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA.

Purpose: Stemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a transcriptional and epigenetic mediator, for TNBC.

Methods: Two independent patient cohorts were subjected to bioinformatic and IHC examination for clinical association of candidate cancer drivers. The efficacy and biological bases for co-targeting these drivers were interrogated using cancer cell lines, a protein kinase array, chemical inhibitors, RNAi/CRISPR/Cas9 approaches, and a 4 T1-Balb/c xenograft model.

Results: We found that amplification of the chromosome 8q24 region occurred in nearly 20% of TNBC tumors, and that it coincided with co-upregulation or amplification of c-Myc and FAK, a key effector of integrin-dependent signaling. This co-upregulation at the mRNA or protein level correlated with a poor patient survival (p < 0.0109 or p < 0.0402, respectively). Furthermore, we found that 14 TNBC cell lines exhibited high vulnerabilities to the combination of JQ1 and VS-6063, potent pharmacological antagonists of the BRD4/c-Myc and integrin/FAK-dependent pathways, respectively. We also observed a cooperative inhibitory effect of JQ1 and VS-6063 on tumor growth and infiltration of Ly6G myeloid-derived suppressor cells in vivo. Finally, we found that JQ1 and VS-6063 cooperatively induced apoptotic cell death by altering XIAP, Bcl2/Bcl-xl and Bim levels, impairing c-Src/p130Cas-, PI3K/Akt- and RelA-associated signaling, and were linked to EMT-inducing transcription factor Snail- and Slug-dependent regulation.

Conclusion: Based on our results, we conclude that the BRD4/c-Myc- and integrin/FAK-dependent pathways act in concert to promote breast cancer cell survival and poor clinical outcomes. As such, they represent promising targets for a synthetic lethal-type of therapy against TNBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13402-020-00537-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716866PMC
December 2020

Epigenetic Input Dictates the Threshold of Targeting of the Integrin-Dependent Pathway in Non-small Cell Lung Cancer.

Front Cell Dev Biol 2020 22;8:652. Epub 2020 Jul 22.

Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United States.

We investigated the therapeutic potential of targeting integrin/FAK-dependent signaling, an adhesion receptor-mediated pathway that has been increasingly linked to non-small cell lung cancer (NSCLC) malignancy. Our analysis of the TCGA cohort showed that a subset of pro-tumorigenic integrins, including α1β1, α2β1, α3β1, α5β1, and α6β4, were frequently amplified or upregulated at the genomic or mRNA level in KRAS or EGFR mutation/overexpression-enriched adenocarcinomas. These alterations appeared complementary, correlated with poor patient survival ( < 0.0072), and were collaborative with KRAS mutation-coupled αv integrins ( < 0.00159). Since integrin/FAK-dependent signaling is tightly coupled with normal human physiology, we sought to use a synthetic lethal-type targeting comprising of VS-6063, a chemical inhibitor of integrin-mediated FAK activity, and A549 cells, which carry a KRAS mutation and EGFR overexpression. Our screening analysis revealed that JQ1 and IBET-762, inhibitors of epigenetic reader BRD4, and LBH589, a pan inhibitor of histone deacetylases (HDACs), exhibited synergy with VS-6063 in mitigating tumor cell viability. This epigenetic link was corroborated by strong effects of additional inhibitors and RNAi-mediated knockdown of FAK and BRD4 or its downstream effector, c-Myc. Low doses of JQ1 (≤0.5 μM) markedly escalated efficacy of VS-6063 across a panel of 10 NSCLC cell lines. This catalyst-like effect is in line with the oncogenic landscape in the TCGA cohort since c-Myc falls downstream of the KRAS and EGFR oncogenes. Mechanistically, co-inhibiting the integrin-FAK and BRD4/c-Myc axes synergistically induced apoptotic cell death and DNA damage response, and impaired stemness-associated tumorsphere formation. These effects were accompanied by a marked inhibition of Akt- and p130Cas/Src-dependent signaling, but not Erk1/2 activity. Meanwhile, JQ1 alone or in combination with VS-6063 attenuated cell-cell adhesion and extracellular matrix (ECM)-dependent cell spreading, which is reminiscent of phenotype induced by malfunctional E-cadherin or integrins. Paradoxically, this phenotypic impact coincided with downregulation of epithelial-mesenchymal transition (EMT)-inducting transcription factor ZEB1 or Snail. Finally, we showed that the effect of the VS-6063/JQ1 combination was nearly equivalent to that of VS-6063 plus Carboplatin or Osimertinib. Overall, our study indicates that the integrin/FAK and BRD4/c-Myc axes cooperatively drive NSCLC virulence, and a co-targeting may provide a line of therapy capable of overcoming EGFR/KRAS-driven malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2020.00652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387701PMC
July 2020

An effective UFLC-MS/MS method used to study pharmacokinetics of major constituents of Fukeqianjin formula in rat plasma.

Chin Med 2020 25;15:74. Epub 2020 Jul 25.

Zhuzhou Qianjin Pharmaceutical Co., Ltd, Zhuzhou, 412000 China.

Background: Fukeqianjin formula (FKQJF) is a Chinese medicine prescription, which has been widely used individually or in combination with other western medicine for the treatment of various gynecological inflammatory diseases, including chronic cervicitis, chronic pelvic inflammatory disease and endometritis, so on and so force.

Methods: The ultra-fast liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UFLC-MS/MS), a quick and efficient method was established and applied to quantify the major constituents of Fukeqianjin formula in rat plasma, and its pharmacokinetics of oral absorption was studied. Nineteen components in Fukeqianjin formula were detected and identified as the major compounds absorbed into the blood according to their chromatographic behavior, molecular weight, ion fragments and other information of these compounds. Furthermore, the plasma drug concentration-time curves were established and the related kinetic parameters were analyzed.

Results: The results showed that all the 19 compounds could be rapidly absorbed by the gastrointestinal tract, the plasma drug concentration of most compounds could reach a peak at around 1-2 h, and the double-peaks on behalf of the enterohepatic circulation were found in most drug concentration-time curves. The method used in this experiment was validated comprehensively including specificity, linearity, precision, accuracy, stability, matrix effect, and recovery.

Conclusions: These results showed that the developed method was suitable for pharmacokinetic analysis of the main components of Fukeqianjin formula in rat plasma, and may provide useful information for the subsequent distribution studies in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13020-020-00347-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382147PMC
July 2020

Identification of candidate tolerance genes to low-temperature during maize germination by GWAS and RNA-seqapproaches.

BMC Plant Biol 2020 Jul 14;20(1):333. Epub 2020 Jul 14.

Key Laboratory of Germplasm Enhancement, Physiology and Ecology of Food Crops in Cold Region, College of Agronomy, Northeast Agricultural University, Harbin, 150030, Heilongjiang, China.

Background: Maize (Zea mays L.) is one of the main agricultural crops with the largest yield and acreage in the world. However, maize germplasm is very sensitive to low temperatures, mainly during germination, and low temperatures significantly affect plant growth and crop yield. Therefore, the identification of genes capable of increasing tolerance to low temperature has become necessary.

Results: In this study, fourteen phenotypic traits related to seed germination were used to assess the genetic diversity of maize through genome-wide association study (GWAS). A total of 30 single-nucleotide polymorphisms (SNPs) linked to low-temperature tolerance were detected (-log10(P) > 4), fourteen candidate genes were found to be directly related to the SNPs, further additional 68 genes were identified when the screen was extended to include a linkage disequilibrium (LD) decay distance of r ≥ 0.2 from the SNPs. RNA-sequencing (RNA-seq) analysis was then used to confirm the linkage between the candidate gene and low-temperature tolerance. A total of ten differentially expressed genes (DEGs) (|log fold change (FC)| ≥ 0.585, P < 0.05) were found within the set distance of LD decay (r ≥ 0.2). Among these genes, the expression of six DEGs was verified using qRT-PCR. Zm00001d039219 and Zm00001d034319 were putatively involved in 'mitogen activated protein kinase (MAPK) signal transduction' and 'fatty acid metabolic process', respectively, based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Thus, these genes appeared to be related to low-temperature signal transduction and cell membrane fluidity.

Conclusion: Overall, by integrating the results of our GWAS and DEG analysis of low-temperature tolerance during germination in maize, we were able to identify a total of 30 SNPs and 82 related candidate genes, including 10 DEGs, two of which were involved in the response to tolerance to low temperature. Functional analysis will provide valuable information for understanding the genetic mechanism of low-temperature tolerance during germination in maize.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12870-020-02543-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362524PMC
July 2020

Integrin-associated CD151 is a suppressor of prostate cancer progression.

Am J Transl Res 2020 15;12(4):1428-1442. Epub 2020 Apr 15.

Department of Pharmacology and Nutritional Sciences, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky Lexington 40536, KY, USA.

Owing to the complexity of interacting molecular networks on the cell surface, integrin-associated tetraspanin CD151 remains controversial regarding its clinical importance and functional impact in prostate cancer. The current study evaluated dynamics and clinical importance of CD151 expression and its function in prostate cancer by IHC analysis of two independent patient cohorts (n=80, 181), bioinformatic interrogation of the TCGA database, and evaluation of gene knockdown effect at the cellular level. Our data showed that aside from high mRNA expression, CD151 was primarily localized to intercellular junctions at the plasma membrane in normal prostate glands or benign tissues, regardless of nature of antibodies used. By contrast, in primary tumors from patients with metastatic disease, CD151 was largely localized in the cytosol. Furthermore, the level of the cell-cell junction-linked CD151 was inversely associated with Gleason grade and tumor stage (P<0.001 for both). The portion of primary tumors expressing junctional CD151 was also three-fold less in the metastatic patient population than its counterpart (P<0.001). In line with these observations, CD151 and its associated α3β1 or α6β4 integrin inversely correlated with androgen receptor (AR) at the mRNA level (Spearman coefficient: -0.44, -0.48 and -0.42) in the TCGA cohort. Expression of these adhesion molecules also correlated with DNA methylation in their promoters (Spearman coefficient: -0.37, -0.71 and -0.82). Combined, these data suggest that CD151 and associated integrins are linked to tumor metastasis through AR and the epigenetic program. Meanwhile, CD151 knockdown in E-cadherin-positive tumor cells led to increased cell proliferation and induction of the epithelial-mesenchymal transition (EMT)-like phenotype. Given the strong RGD-binding integrin dependence of EMT-featured tumor cells, we examined focal adhesion kinase (FAK), their key signaling effector, in the above patient cohorts. In contrast to CD151, FAK exhibited positive correlation with tumor grade and stage as well as AR and p53 inactivation at either mRNA, protein or genomic level. Taken together, our results suggest that CD151 represses prostate cancer by antagonizing cell proliferation, EMT and the signaling of RGD-binding integrins. Since this anti-tumorigenic role is prone to the AR-mediated transcriptional and epigenetic regulation, CD151 and possibly α3β1 and α6β4 integrins are of potential biomarkers for metastatic prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191174PMC
April 2020

Alpinumisoflavone suppresses hepatocellular carcinoma cell growth and metastasis via NLRP3 inflammasome-mediated pyroptosis.

Pharmacol Rep 2020 Oct 3;72(5):1370-1382. Epub 2020 Mar 3.

The Affiliated Hospital of Qingdao University, Jiangsu Road 16, Qingdao, 266003, China.

Aim: This research aims to explore the effect of alpinumisoflavone (AIF) as an anti-cancer drug for the treatment of patients with hepatocellular carcinoma (HCC).

Methods: Cell counting kit-8 (CCK-8) and colony formation assay were used to evaluate the viability of the cells and their clonogenic ability. Cellular migration and their invasion capabilities were detected using the wound-healing and transwell assay, respectively. The release of lactate dehydrogenase (LDH) was detected using the LDH kit. The expression levels of genes in the cells and tumor tissues were examined by qRT-PCR, western blotting, and immunohistochemical techniques. The cells transfected with mRFP-GFP-LC3 adenoviruses were stained to determine their autophagy status. MCC950 (NLRP3 inflammasome inhibitor) and NLRP3 shRNA were used to block NLRP3-mediated pyroptosis. Chloroquine and Atg 5 siRNA were used to inhibit the autophagy of the cells.

Results: AIF suppressed cell proliferation, migration, and invasion capacity of SMMC 7721 and Huh7 cells. The incorporation of AIF induced the formation of NLRP3 inflammasome assembly, pyroptosis, and autophagy of the cells. However, the anti-proliferative and anti-metastatic effects of AIF on the HCC cells were attenuated by NLRP3 inhibitor and knockdown. Furthermore, Atg 5 knockdown inhibited autophagy and enhanced the rate of AIF-induced pyroptosis of the cells. AIF also suppressed tumor growth and increased the levels of pyroptosis-related genes in tumor tissues, which were consistent with in vitro observations.

Conclusion: AIF inhibited HCC cell growth and metastasis by inducing NLRP3 inflammasome-mediated pyroptosis. Furthermore, AIF-induced autophagy augmented pyroptosis in HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s43440-020-00064-8DOI Listing
October 2020

The combined effect of epigenetic inhibitors for LSD1 and BRD4 alters prostate cancer growth and invasion.

Aging (Albany NY) 2020 01 5;12(1):397-415. Epub 2020 Jan 5.

Department of Pharmacology and Nutrition Science, The University of Kentucky, Lexington, KY 40506, USA.

Epigenetic modifications play an important role in prostate tumor development and progression. Epigenetic drugs are emerging as effective modulators of gene expression that act on pathways potentially important in the control of cancer clinically. We investigated two different epigenetic modulating drugs, SP-2509 and JQ1, that target histone lysine demethylase 1 (LSD1), and bromodomain-containing protein (BRD), respectively and their combined effect in three different prostate cancer (PCa) types: 1) androgen receptor (AR)-positive and androgen-sensitive; 2) AR-positive but castration-resistant; and 3) androgen-nonresponsive. We found combined treatment provided a synergistic growth inhibition in castration-resistant PCa cells but knockdown of AR reduced sensitivity to both inhibitors in these cells. In the androgen-sensitive cell lines, AR knockdown attenuated sensitivity to the LSD1 inhibitor but not the JQ1 inhibitor. Strikingly, treatment with SP-2509 slightly, and JQ1 markedly increased invasion in PCa cells with high AR expression but decreased invasion in PCa cells with low/negative AR expression. Our results suggest that these two epigenetic drugs are novel and promising compounds for the development of PCa therapeutics, particularly for castration-resistant disease. However, due to the potential risks, including metastasis, caution must be exercised in the clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.102630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977660PMC
January 2020

Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis.

Free Radic Biol Med 2020 02 23;148:33-41. Epub 2019 Dec 23.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address:

Inflammatory bowel disease (IBD) represents a group of chronic relapsing intestinal disorders. Rutaecarpine (RUT), isolated from the Traditional Chinese Medicine (TCM) of Evodia rutaecarpa, was reported to suppress IBD. However, the mechanism by which RUT ameliorates dextran sulfate sodium (DSS)-induced IBD is largely unknown. By use of nuclear factor-erythroid 2-related factor 2 (NRF2) knockout mice, cell-based studies, surface plasmon resonance (SPR), western blotting analysis, and molecular docking studies, the mechanism by which RUT affects DSS-induced colitis was explored. In DSS-treated wild-type mice but not in Nrf2-null mice, RUT significantly improved colitis as revealed by rescued body weight loss, improved histology and inflammation, and induced expression of NRF2 target genes in colon and ileum. Cell-based studies showed that RUT significantly increased the LD for hydrogen peroxide (HO)-induced cell damage, activated NRF2 nuclear translocation, and suppressed the production of reactive oxygen species in HO-treated HCT116 cells, activated NRF2 luciferase reporter activities in HCT116 cells and HepG2 cells, and induced expression of NRF2 target genes in primary intestinal epithelial cells. Molecular docking in silico and SPR assays indicated that RUT interacted with kelch-like ECH-associated protein 1 (KEAP1), and extracellular incubation studies revealed that RUT bound to the KEAP1 kelch domain with a calculated equilibrium dissociation constant K of 19.6 μM. In conclusion, these results demonstrate that RUT ameliorates DSS-induced colitis, dependent on NRF2, and could be a potential therapeutic option for IBD patients. Mechanistically, RUT potentiates NRF2 nuclear translocation to upregulate NRF2-mediated antioxidant response by directly inhibiting KEAP1-NRF2 interaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.freeradbiomed.2019.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376370PMC
February 2020

Deletion of tetraspanin CD151 alters the Wnt oncogene-induced mammary tumorigenesis: A cell type-linked function and signaling.

Neoplasia 2019 12 26;21(12):1151-1163. Epub 2019 Nov 26.

Department of Pharmacology and Nutritional Sciences, Department of Molecular and Cellular Biochemistry, Markey Cancer Center, University of Kentucky, Lexington, KY. Electronic address:

Tetraspanin CD151 is increasingly implicated as a multifaceted mediator of cancer development and progression. Here we investigated the role of CD151 in breast cancer in the context of the Wnt oncogenic activation. Our data showed that removal of one or both of CD151 alleles in the MMTV-Wnt1 model significantly decreased the tumor-free survival of mice from 34 weeks on average to 22 weeks and 18 weeks, respectively. This effect coincided with an accelerated tumor growth and an increased number of Ki-67 proliferative cells. Mechanistically, the CD151-deficient tumors were largely ER, and exhibited hyperactivation of the Wnt pathway as reflected by a marked upregulation in β-catenin and Cyclin D1, and their target genes. In addition, E-cadherin displayed a cytosolic distribution and transcription factor Snail was markedly upregulated. Collectively, this data implies that CD151 suppresses the Wnt1-driven tumorigenesis, at least in part, via counteracting the epithelial-mesenchymal transition (EMT)-like program in luminal epithelial cells. Meanwhile, the proportion of tumor cells expressing CK5 or p63, the biomarkers of myoepithelial/basal cells, markedly decreased in the absence of CD151. This change was accompanied by a decreased invasiveness of tumors and their incompetence to form a long-term cell culture. Consistent with this basal cell-linked role, the CD151 downregulation impairs mammosphere formation in MCF-10A cells and the defect was rescued by re-expression of intact CD151 ORF, but not its integrin binding-defective mutant. Overall, our study suggests that CD151 is a key player in the Wnt oncogene-driven tumorigenesis and impacts breast cancer malignancy in a cell type-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neo.2019.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888732PMC
December 2019

Downregulation of microRNA‑183‑5p inhibits the proliferation and invasion of colorectal cancer cells by inactivating the reticulocalbin‑2/Wnt/β‑catenin signaling pathway.

Mol Med Rep 2019 May 19;19(5):4475-4483. Epub 2019 Mar 19.

Department of Gastrointestinal Surgery, The Second People's Hospital of Lianyungang, Haizhou, Jiangsu 310000, P.R. China.

microRNAs (miRNAs) are frequently aberrantly expressed in colorectal cancer (CRC) and are considered to serve a critical role in the onset and development of CRC by binding to its target transcription factor. The aim of the present study was to examine the role of miRNA (miR)‑183‑5p in the proliferation, invasion and migration of CRC cells, in addition to its underlying mechanism. Reverse transcription‑quantitative polymerase chain reaction analysis was used to detect the expression level of miR‑183‑5p. MTT and Transwell assays were performed to examine proliferation and invasion in SW620 cells. Western blot analysis was performed to determine the protein expression of reticulocalbin‑2 (RCN2), matrix metalloproteinase‑2, β‑catenin, cyclin D1 and c‑Myc. miR‑183‑5p expression was significantly upregulated in the CRC tissues compared with adjacent normal tissues. In addition, the inhibition of miR‑183‑5p suppressed proliferation, invasion and migration in SW620 cells. miR‑183‑5p downregulation or overexpression regulated the CRC cell cycle, invasion and migration by modulating RCN2 expression. Furthermore, the Wnt/β‑catenin pathway was observed to be involved in the inhibitory effect of miR‑183‑5p downregulation in CRC cell proliferation, invasion and migration. These results provided evidence that the downregulation of miR‑183‑5p inhibits CRC proliferation and invasion by regulating the RCN2/Wnt/β‑catenin pathway. miR‑183‑5p and RCN2 may serve an important role in the molecular etiology of CRC and have potential applications in CRC treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/mmr.2019.10059DOI Listing
May 2019

Autophagy induction by xanthoangelol exhibits anti-metastatic activities in hepatocellular carcinoma.

Cell Biochem Funct 2019 Apr 18;37(3):128-138. Epub 2019 Mar 18.

China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.

Xanthoangelol (XAG), a prenylated chalcone isolated from the Japanese herb Angelica keiskei Koidzumi, has been reported to exhibit antineoplastic properties. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC), and the relevant mechanisms are not known. Herein, we evaluated the effect of XAG against HCC in vitro and in vivo. Although XAG treatment did not significantly reduce the viability of the Hep3B and Huh7 cell lines, it suppressed cell migration, invasion, and EMT. This anti-metastatic effect of XAG was due to induction of autophagy, because treatment with the autophagy inhibitor 3-methyadenine (3-MA) or knockdown of the pro-autophagy Beclin-1 effectively abrogated the XAG-induced suppression of metastasis. Mechanistically, XAG induced autophagy via activation of the AMPK/mTOR signaling pathway, and XAG treatment dramatically increased the expression of p-AMPK while decreasing p-mTOR expression. In addition, blocking AMPK/mTOR axis with compound C abrogated the autophagy-mediated inhibition of metastasis. The murine model of HCC metastasis also showed that XAG effectively reduced the number of metastatic pulmonary nodules. Taken together, our results revealed that autophagy via the activation of AMPK/mTOR pathway is essential for the anti-metastatic effect of XAG against HCC. These findings not only contribute to our understanding of the anti-tumor activity of XAG but also provide a basis for its clinical application in HCC. Before this study, evidence of XAG on HCC was purely anecdotal; present study provides the first comprehensive assessments of XAG on HCC metastasis and investigates its underlying mechanism. Results suggest that XAG exerts anti-metastatic properties against HCC through inducing autophagy which is mediated by the activation of AMPK/mTOR signaling pathway. This research extends our knowledge about the antineoplastic properties of XAG and suggests that induction autophagy may represent future treatment strategies for metastatic HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbf.3374DOI Listing
April 2019

The metastasis suppressor NME1 inhibits melanoma cell motility via direct transcriptional induction of the integrin beta-3 gene.

Exp Cell Res 2019 01 17;374(1):85-93. Epub 2018 Nov 17.

Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland-Baltimore, Baltimore, MD, United States; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland-Baltimore, Baltimore, MD, United States. Electronic address:

Expression of the metastasis suppressor NME1 in melanoma is associated with reduced cellular motility, invasion, and metastasis, but mechanisms underlying these activities are not completely understood. Herein we report a novel mechanism through which NME1 drives formation of large, stable focal adhesions (FAs) in melanoma cells via induction of integrin β3 (ITGβ3), and in one cell line, concomitant suppression of integrin β1 (ITGβ1) transcripts. Forced expression of NME1 resulted in a strong activation of the promoter region (-301 to +13) of the ITGB3 gene. Chromatin immunoprecipitation (ChIP) analysis revealed the transcriptional induction was associated with direct recruitment of NME1 and an increase in the epigenetic activation mark, acetylation of histone 3 on lysine 27 (H3K27Ac) to a 1 kb stretch of 5'-flanking sequence of the ITGB3 gene. Unexpectedly, NME1 did not affect the amount either ITGβ1 or ITGβ3 proteins were internalized and recycled, processes commonly associated with regulating expression of integrins at the cell surface. The ability of NME1 to suppress motile and invasive phenotypes of melanoma cells was dependent on its induction of ITGβ3. Expression of ITGβ3 mRNA was associated with increased disease-free survival time in melanoma patients of the TCGA collection, consistent with its potential role as an effector of the metastasis suppressor function of NME1. Together, these data indicate metastasis suppressor activity of NME1 in melanoma is mediated by induction of ITGB3 gene transcription, with NME1-driven enrichment of ITGβ3 protein at the cell membrane resulting in attenuated cell motility through the stabilization of large focal adhesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yexcr.2018.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446928PMC
January 2019

Isobavachalcone sensitizes cells to E2-induced paclitaxel resistance by down-regulating CD44 expression in ER+ breast cancer cells.

J Cell Mol Med 2018 11 4;22(11):5220-5230. Epub 2018 Sep 4.

Department of Oncology, Nanjing First Hospital, NanJing Medical University, Nanjing, China.

Oestrogen receptor (ER) is expressed in approximately 60%-70% of human breast cancer. Clinical trials and retrospective analyses have shown that ER-positive (ER+) tumours are more tolerant to chemotherapeutic drug resistance than ER-negative (ER-) tumours. In addition, isobavachalcone (IBC) is known as a kind of phytoestrogen with antitumour effect. However, the underlying mechanism of IBC in ER+ breast cancer needs to be elucidated further. Our in vitro experiments showed that IBC could attenuate 17β-estradiol (E )-induced paclitaxel resistance and that E could stimulate CD44 expression in ER+ breast cancer cells but not in ER- cells. Meanwhile, E could promote ERα expression to render ER+ breast cancer cells resistant to paclitaxel. Furthermore, we established paclitaxel-resistant breast cancer cell lines and determined the function of ERα in the enhancement of paclitaxel resistance via the regulation of CD44 transcription. IBC down-regulated ERα and CD44 expression and thus inhibited tumour growth in paclitaxel-resistant xenograft models. Overall, our data demonstrated for the first time that IBC could decrease CD44 expression level via the ERα pathway and make ER+ breast cancer cells sensitive to paclitaxel treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.13719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201375PMC
November 2018

The diagnostic, prediction of postoperative recurrence and prognostic value of HE4 in epithelial ovarian cancer.

J BUON 2018 Mar-Apr;23(2):428-432

Department of Gynecology, the First People's Hospital of Kashi Prefecture, Xinjiang Uygur Autonomous Region, China.

Purpose: To explore the clinical value of the level of human epididymis protein 4 (HE4) in serum in the diagnosis, prediction of postoperative recurrence and prognosis of epithelial ovarian cancer (EOC).

Methods: A total of 103 EOC patients and 121 individuals with benign ovarian lesions were selected. All of them were admitted to our hospital between January 2013 and January 2014 as group A (EOC, n=103) and group B (benign ovarian lesions, n=121), respectively. Additionally, 106 serum samples collected from healthy people who underwent physical examination were selected as group C. The serum levels of HE4 were assessed one day before and one day after the operation to reveal differences among the three groups. In addition, we analyzed the clinical value of HE4 in the diagnosis, prediction of recurrence and progression-free survival (PFS) of EOC patients.

Results: In group A, the level of HE4 was significantly higher than in groups B and C (p<0.05), while comparison between the group B and C revealed no statistically significant difference (p>0.05). The sensitivity, specificity, positive predictive value and negative predictive value of HE4 in the diagnosis of EOC were 82.52, 84.46, 83.47 and 92.34%, respectively. In the prediction of recurrence of EOC, the sensitivity and specificity of HE4 alone were 87.57 and 92.45%, respectively, while the sensitivity and specificity of HE4 combined with CA-125 were 93.45 and 94.24%, respectively. In addition, the level of HE4 showed a significant negative effect on PFS (p<0.05).

Conclusions: Detection of HE4 is conducive to the diagnosis and prediction of recurrence of EOC, and HE4 in high concentration suggests poor prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2019

Structure-Activity Relationships of the Main Bioactive Constituents of on Aryl Hydrocarbon Receptor Activation and Associated Bile Acid Homeostasis.

Drug Metab Dispos 2018 07 24;46(7):1030-1040. Epub 2018 Apr 24.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Yo.Z., Ti.Y., D.S. C.X., To.Y., K.W.K., F.J.G.); State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing, China (Yo.Z., Yi.Z., L.Z., X.Y.); Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon (W.H.B.); and College of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, Liaoning, China (D.S.)

Rutaecarpine (RUT), evodiamine (EOD), and dehydroevodiamine (DHED) are the three main bioactive indoloquinazoline alkaloids isolated from , a widely prescribed traditional Chinese medicine. Here, the structure-activity relationships of these analogs for aryl hydrocarbon receptor (AHR) activation were explored by use of -deficient () mice, primary hepatocyte cultures, luciferase reporter gene assays, in silico ligand-docking studies, and metabolomics. In vitro, both mRNA analysis of AHR target genes in mouse primary hepatocytes and luciferase reporter assays in hepatocarcinoma cell lines demonstrated that RUT, EOD, and DHED significantly activated AHR, with an efficacy order of RUT > DHED > EOD. Ligand-docking analysis predicted that the methyl substitute at the N-14 atom was a key factor affecting AHR activation. In vivo, EOD was poorly orally absorbed and failed to activate AHR, whereas RUT and DHED markedly upregulated expression of the hepatic AHR gene battery in wild-type mice, but not in mice. Furthermore, RUT, EOD, and DHED were not hepatotoxic at the doses used; however, RUT and DHED disrupted bile acid homeostasis in an AHR-dependent manner. These findings revealed that the methyl group at the N-14 atom of these analogs and their pharmacokinetic behaviors were the main determinants for AHR activation, and suggest that attention should be given to monitoring bile acid metabolism in the clinical use of .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/dmd.117.080176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003592PMC
July 2018

Alpinumisoflavone induces apoptosis in esophageal squamous cell carcinoma by modulating miR-370/PIM1 signaling.

Am J Cancer Res 2016 1;6(12):2755-2771. Epub 2016 Dec 1.

92196 Military Hospital Qingdao 266011, Shandong, China.

Esophageal squamous cell carcinoma (ESCC) is the most prevalent type of esophageal cancer and accumulating evidence has confirmed the role of miRNAs in ESCC. One such miRNA, miR-370, was found to be aberrantly downregulated in various human malignancies. This study showed that the expression of miR-370 was significantly lower in ESCC tissues and cell lines, and miR-370 functioned as a tumor suppressor in ESCC. Moreover, this is the first report that showed miR-370 suppresses cell proliferation and tumor growth by directly targeting Pim family kinases 1 (PIM1). Furthermore, alpinumisoflavone, a naturally occurring flavonoid, could inhibit tumor growth of ESCC by targeting miR-370/PIM1 signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199752PMC
December 2016

Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38γ.

Oncotarget 2016 Jan;7(3):3489-505

Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA.

Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12-48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the scattering of MCF7, BT20 and T47D cell colonies in a 3-dimension culture system. Chronic ethanol exposure also increased colony formation in an anchorage-independent condition and stimulated cell invasion/migration. Chronic ethanol exposure increased cancer stem-like cell (CSC) population by more than 20 folds. Breast cancer cells exposed to ethanol in vitro displayed a much higher growth rate and metastasis in mice. Ethanol selectively activated p38γ MAPK and RhoC but not p38α/β in a concentration-dependent manner. SP-MCF7 cells, a derivative of MCF7 cells which compose mainly CSC expressed high levels of phosphorylated p38γ MAPK. Knocking-down p38γ MAPK blocked ethanol-induced RhoC activation, cell scattering, invasion/migration and ethanol-increased CSC population. Furthermore, knocking-down p38γ MAPK mitigated ethanol-induced tumor growth and metastasis in mice. These results suggest that chronic ethanol exposure can enhance the aggressiveness of breast cancer by activating p38γ MAPK/RhoC pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.6508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823122PMC
January 2016

CD151-α3β1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion.

Oncotarget 2015 Oct;6(30):29675-93

Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.

Glioblastoma, one of the most aggressive forms of brain cancer, is featured by high tumor cell motility and invasiveness, which not only fuel tumor infiltration, but also enable escape from surgical or other clinical interventions. Thus, better understanding of how these malignant traits are controlled will be key to the discovery of novel biomarkers and therapies against this deadly disease. Tetraspanin CD151 and its associated α3β1 integrin have been implicated in facilitating tumor progression across multiple cancer types. How these adhesion molecules are involved in the progression of glioblastoma, however, remains largely unclear. Here, we examined an in-house tissue microarray-based cohort of 96 patient biopsies and TCGA dataset to evaluate the clinical significance of CD151 and α3β1 integrin. Functional and signaling analyses were also conducted to understand how these molecules promote the aggressiveness of glioblastoma at molecular and cellular levels. Results from our analyses showed that CD151 and α3 integrin were significantly elevated in glioblastomas at both protein and mRNA levels, and exhibited strong inverse correlation with patient survival (p < 0.006). These adhesion molecules also formed tight protein complexes and synergized with EGF/EGFR to accelerate tumor cell motility and invasion. Furthermore, disruption of such complexes enhanced the survival of tumor-bearing mice in a xenograft model, and impaired activation of FAK and small GTPases. Also, knockdown- or pharmacological agent-based attenuation of EGFR, FAK or Graf (ARHGAP26)/small GTPase-mediated pathways markedly mitigated the aggressiveness of glioblastoma cells. Collectively, our findings provide clinical, molecular and cellular evidence of CD151-α3β1 integrin complexes as promising prognostic biomarkers and therapeutic targets for glioblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.4896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745755PMC
October 2015

Role of MCP-1 in alcohol-induced aggressiveness of colorectal cancer cells.

Mol Carcinog 2016 May 25;55(5):1002-11. Epub 2015 May 25.

Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky.

Epidemiological studies demonstrate that alcohol consumption is associated with an increased risk of colorectal cancer (CRC). In addition to promoting carcinogenesis, alcohol may also accelerate the progression of existing CRC. We hypothesized that alcohol may enhance the aggressiveness of CRC. In this study, we investigated the effect of alcohol on the migration/invasion and metastasis of CRC. Alcohol increased the migration/invasion of colorectal cancer cells (DLD1, HCT116, HT29, and SW480) in a concentration-dependent manner. Among these colon cancer cell lines, HCT116 cells were most responsive while HT29 cells were the least responsive to ethanol-stimulated cell migration/invasion. These in vitro results were supported by animal studies which demonstrated that ethanol enhanced the metastasis of colorectal cancer cells to the liver and lung. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays an important role in regulating tumor microenvironment and metastasis. Alcohol increased the expression of MCP-1 and its receptor CCR2 at both protein and mRNA levels. The pattern of alcohol-induced alterations in MCP-1 expression was consistent with its effect on migration/invasion; HCT116 cells displayed the highest up-regulation of MCP-1/CCR2 in response to alcohol exposure. An antagonist of CCR2 blocked alcohol-stimulated migration. Alcohol caused an initial cytosolic accumulation of β-catenin and its subsequent nuclear translocation by inhibiting GSK3β activity. Alcohol stimulated the activity of MCP-1 gene promoter in a β-catenin-dependent manner. Furthermore, knock-down of MCP-1/CCR2 or β-catenin was sufficient to inhibit alcohol-induced cell migration/invasion. Together, these results suggested that alcohol may promote the metastasis of CRC through modulating GSK3β/β-catenin/MCP-1 pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mc.22343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659775PMC
May 2016

Metastasis suppressor NME1 regulates melanoma cell morphology, self-adhesion and motility via induction of fibronectin expression.

Exp Dermatol 2015 Jun 27;24(6):455-61. Epub 2015 Apr 27.

Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, School of Medicine, University of Maryland-Baltimore, Baltimore, MD, USA.

Expression of the metastasis suppressor NME1 in melanoma is associated with reduced cellular motility and invasion in vitro and metastasis in vivo, but the underlying molecular mechanisms are not completely understood. Herein, we report a novel mechanism through which NME1 controls melanoma cell morphology via upregulation of the extracellular matrix (ECM) protein fibronectin. Expression of NME1 strongly suppressed cell motility in melanoma cell lines 1205LU and M14. The resulting sedentary phenotype was associated with a more flattened appearance and marked increases in actin stress fibre and focal adhesion formation. NME1-induced focal adhesions were colocalized with dense deposits of fibronectin, which were absent or minimal in the corresponding NME1-deficient parental lines. NME1 was a strong inducer of fibronectin mRNA and protein expression, shown with reciprocal approaches of forced NME1 expression and shRNA-mediated knock-down. Increased synthesis and ECM deposition of fibronectin was necessary for NME1-induced cell spreading, as knock-down of fibronectin opposed the effects of NME1 on cell morphology. Fibronectin knock-down also reversed the ability of NME1 to promote aggregation when cells were plated on a non-adherent substratum. Similarly, inhibiting activation of the fibronectin receptor integrin α4β1 with an anti-α4 antibody reversed the motility-suppressing effect of NME1. A positive correlation was observed between NME1 and fibronectin mRNA in clinical biopsies of normal skin, benign nevi and primary melanomas, but not in metastatic forms, suggesting the NME1/fibronectin axis represents a barrier to melanoma progression. In summary, these findings indicate fibronectin is an important effector of the motility-suppressing function of NME1 in melanoma cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.12697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437809PMC
June 2015
-->