Publications by authors named "Mee-Hyun Lee"

109 Publications

Challenge and countermeasures for EGFR targeted therapy in non-small cell lung cancer.

Biochim Biophys Acta Rev Cancer 2021 Nov 15;1877(1):188645. Epub 2021 Nov 15.

Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China. Electronic address:

Lung cancer causes the highest mortality compared to other cancers in the world according to the latest WHO reports. Non-small cell lung cancer (NSCLC) contributes about 85% of total lung cancer cases. An extensive number of risk factors are attributed to the progression of lung cancer. Epidermal growth factor receptor (EGFR), one of the most frequently mutant driver genes, is closely involved in the development of lung cancer through regulation of the PI3K/AKT and MAPK pathways. As a representative of precision medicine, EGFR-tyrosine kinase inhibitors (TKIs) targeted therapy significantly relieves the development of activating mutant EGFR-driven NSCLC. However, treatment with TKIs facilitates the emergence of acquired resistance that continues to pose a significant hurdle with respect to EGFR targeted therapy. In this review, the development of current approved EGFR-TKIs as well as the related supporting clinical trials are summarized and discussed. Mechanisms of action and resistance were addressed respectively, which serve as important guides to understanding acquired resistance. We also explored the corresponding combination treatment options according to different resistance mechanisms. Future challenges include more comprehensive characterization of unclear resistance mechanisms in different populations and the development of more efficient and precision synthetic therapeutic strategies.
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http://dx.doi.org/10.1016/j.bbcan.2021.188645DOI Listing
November 2021

Podophyllotoxin Induces ROS-Mediated Apoptosis and Cell Cycle Arrest in Human Colorectal Cancer Cells via p38 MAPK Signaling.

Biomol Ther (Seoul) 2021 Nov;29(6):658-666

Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan 58554, Republic of Korea.

Podophyllotoxin (PT), a lignan compound from the roots and rhizomes of , has diverse pharmacological activities including anticancer effect in several types of cancer. The molecular mechanism of the anticancer effects of PT on colorectal cancer cells has not been reported yet. In this study, we sought to evaluate the anticancer effect of PT on human colorectal cancer HCT116 cells and identify the detailed molecular mechanism. PT inhibited the growth of cells and colony formation in a concentration-dependent manner and induced apoptosis as determined by the annexin V/7-aminoactinomycin D double staining assay. PT-induced apoptosis was accompanied by cell cycle arrest in the G2/M phase and an increase in the generation of reactive oxygen species (ROS). The effects of PT on the induction of ROS and apoptosis were prevented by pretreatment with N-acetyl-L-cysteine (NAC), indicating that an increase in ROS generation mediates the apoptosis of HCT116 cells induced by PT. Furthermore, Western blot analysis showed that PT upregulated the level of phospho (p)-p38 mitogen-activated protein kinase (MAPK). The treatment of SB203580, a p38 inhibitor, strongly prevented the apoptosis induced by PT, suggesting that PT-induced apoptosis involved the p38 MAPK signaling pathway. In addition, PT induced the loss of mitochondrial membrane potential and multi-caspase activation. The results suggested that PT induced cell cycle arrest in the G2/M phase and apoptosis through the p38 MAPK signaling pathway by upregulating ROS in HCT116 cells.
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http://dx.doi.org/10.4062/biomolther.2021.143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551740PMC
November 2021

Picropodophyllotoxin induces G1/S cell cycle arrest and apoptosis in human colorectal cancer cells via ROS generation and activation of p38 MAPK signaling pathway.

J Microbiol Biotechnol 2021 Sep 15;31(1). Epub 2021 Sep 15.

Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea.

Picropodophyllotoxin (PPT), an epimer of podophyllotoxin, is derived from the roots of and it exerts various biological effects, such as anti- proliferation activity. However, the effect of PPT on colorectal cancer cells and the cellular mechanisms have not been studied. In the present study, we explored the anticancer activity and its underlying mechanisms of PPT in HCT116 cells. The MTT assay was used to monitor the cell viability. The flow cytometry was used to evaluate cell cycle distribution, induction of apoptosis, level of reactive oxygen species (ROS), assessment of the mitochondrial membrane potential (Δψm) and multi-caspase activity. western blotting assay was performed to detect the expression of cell cycle regulatory proteins, apoptosis-related proteins, and p38MAPK. We found that PPT induced apoptosis, cell cycle arrest at the G1-phase, and reactive oxygen species production in HCT116 cell line. In addition, PPT enhanced phosphorylation of p38 MAPK that regulates apoptosis and PPT induced apoptosis. The phosphorylation of p38 MAPK was inhibited by antioxidant agent (-acetyl-L-cysteine, NAC) and the p38 inhibitor (SB203580). PPT induced depolarization of the mitochondrial inner membrane and caspase dependent apoptosis, which was attenuated by exposure to Z VAD FMK. Overall, these data indicate that PPT induces G1/S arrest and apoptosis via the ROS generation and activation of p38 MAPK signaling pathway.
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http://dx.doi.org/10.4014/jmb.2109.09012DOI Listing
September 2021

Costunolide Induces Apoptosis via the Reactive Oxygen Species and Protein Kinase B Pathway in Oral Cancer Cells.

Int J Mol Sci 2021 Jul 13;22(14). Epub 2021 Jul 13.

Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, Sangju 37224, Korea.

Oral cancer (OC) has been attracted research attention in recent years as result of its high morbidity and mortality. Costunolide (CTD) possesses potential anticancer and bioactive abilities that have been confirmed in several types of cancers. However, its effects on oral cancer remain unclear. This study investigated the potential anticancer ability and underlying mechanisms of CTD in OC in vivo and in vitro. Cell viability and anchorage-independent colony formation assays were performed to examine the antigrowth effects of CTD on OC cells; assessments for migration and invasion of OC cells were conducted by transwell; Cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. The results revealed that CTD suppressed the proliferation, migration and invasion of oral cancer cells effectively and induced cell cycle arrest and apoptosis; regarding the mechanism, CTD bound to AKT directly by binding assay and repressed AKT activities through kinase assay, which thereby downregulating the downstream of AKT. Furthermore, CTD remarkably promotes the generation of reactive oxygen species by flow cytometry assay, leading to cell apoptosis. Notably, CTD strongly suppresses cell-derived xenograft OC tumor growth in an in vivo mouse model. In conclusion, our results suggested that costunolide might prevent progression of OC and promise to be a novel AKT inhibitor.
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http://dx.doi.org/10.3390/ijms22147509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305390PMC
July 2021

Vitamin C alleviates hyperuricemia nephropathy by reducing inflammation and fibrosis.

J Food Sci 2021 Jul 23;86(7):3265-3276. Epub 2021 Jun 23.

School of Food Science and Technology, Jiangnan University, Wuxi, China.

Hyperuricemia contributes to chronic kidney disease development. However, it has been historically viewed with limited research interest. In this study, we mimicked the development of hyperuricemic nephropathy by using a potassium oxonate-induced hyperuricemia rat model. We found that administering vitamin C at 10 mg/kg/day effectively ameliorated hyperuricemic nephropathy. Compared to the control group, rats with hyperuricemia had significantly increased serum uric acid level, xanthine oxidase activity, and urine microalbumin level, by 5-fold, 1.5-fold, and 4-fold, respectively. At the same time, vitamin C supplementation reverted these values by 20% for serum uric acid level and xanthine oxidase activity and 50% for microalbumin level. Vitamin C also alleviated renal pathology and decreased the expression of pro-inflammatory and pro-fibrotic markers. A further mechanistic study suggested that vitamin C might attenuate hyperuricemic nephropathy in renal tubular epithelial cells induced by monosodium urate (MSU) crystal, at least in part, by directly inhibiting IL-6/JAK2/STAT3 signaling pathway. Meanwhile, in macrophages, vitamin C inhibited the expression of TGF-β, and reduced ROS level induced by MSU by about 35%. In short, our results suggest that vitamin C supplementation delay the progression of hyperuricemic nephropathy.
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http://dx.doi.org/10.1111/1750-3841.15803DOI Listing
July 2021

Heterogeneity Analysis of Esophageal Squamous Cell Carcinoma in Cell Lines, Tumor Tissues and Patient-Derived Xenografts.

J Cancer 2021 10;12(13):3930-3944. Epub 2021 May 10.

Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, China.

Esophageal Squamous Cell Carcinoma (ESCC) is the predominant type of Esophageal Cancer (EC), accounting for nearly 88% of EC incidents worldwide. Importantly, it is also a life-threatening cancer for patients diagnosed in advanced stages, with only a 20% 5-year survival rate due to a limited number of actionable targets and therapeutic options. Increasing evidence has shown that inter-tumor and intra-tumor heterogeneity are widely distributed across ESCC tumor tissues. In our work, multi-omics data from ESCC cell lines, tumor tissue, normal tissue and Patient-Derived Xenograft (PDX) tissues were analyzed to investigate the heterogeneity among ESCC samples at the DNA, RNA, and protein level. We identified enrichment of ECM-receptor interaction and Focal adhesion pathways from the subset of protein-coding genes with non-silent mutations in ESCC patients. We also found that , , , , , and are the most frequently mutated genes in ESCC patient samples. Out of the identified genes, is the most frequently mutated, with 84 distinct non-silent mutation variants. We observed that p.R248Q, p.R175G/H, and p.R273C/H are the most common mutation variants. The diversity of mutations reveal its importance in ESCC progression and may also provide promising targets for precision therapeutics. Additionally, we identified the Olfactory transduction as the top signaling pathway, enriched from genes uniquely expressed in The Cancer Genome Atlas (TCGA)-ESCC patient tumor tissues, which may provide implications for the exact roles of the corresponding genes in ESCC. Cyclic nucleotide-gated channel subunit beta 1(CNGB1), a gene belonging to the Olfactory transduction pathway, was found exclusively overexpressed in ESCC. Expression of CNGB1 could serve as a marker, indicating potential diagnostic or therapeutic value. Finally, we investigated heterogeneity in the context of the ESCC PDX model, which is an emerging tool used to predict drug response and recapitulate tumor behavior . We observed trans-species heterogeneity in as high as 75% of the identified proteins, indicating that the ambiguity of proteins should be addressed by specific strategies to avoid drawing false conclusions. The identification and characterization of gene mutation and expression heterogeneity across different ESCC datasets, including various novel mutations, ECM-receptor interaction, Focal adhesion, and Olfactory transduction pathways (), provide researchers with evidence and implications for accurate research and precision therapeutic development.
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http://dx.doi.org/10.7150/jca.52286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176252PMC
May 2021

PBK/TOPK: An Effective Drug Target with Diverse Therapeutic Potential.

Cancers (Basel) 2021 May 6;13(9). Epub 2021 May 6.

Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, Sangju 37224, Korea.

T-lymphokine-activated killer cell-originated protein kinase (TOPK, also known as PDZ-binding kinase or PBK) plays a crucial role in cell cycle regulation and mitotic progression. Abnormal overexpression or activation of TOPK has been observed in many cancers, including colorectal cancer, triple-negative breast cancer, and melanoma, and it is associated with increased development, dissemination, and poor clinical outcomes and prognosis in cancer. Moreover, TOPK phosphorylates p38, JNK, ERK, and AKT, which are involved in many cellular functions, and participates in the activation of multiple signaling pathways related to MAPK, PI3K/PTEN/AKT, and NOTCH1; thus, the direct or indirect interactions of TOPK make it a highly attractive yet elusive target for cancer therapy. Small molecule inhibitors targeting TOPK have shown great therapeutic potential in the treatment of cancer both in vitro and in vivo, even in combination with chemotherapy or radiotherapy. Therefore, targeting TOPK could be an important approach for cancer prevention and therapy. Thus, the purpose of the present review was to consider and analyze the role of TOPK as a drug target in cancer therapy and describe the recent findings related to its role in tumor development. Moreover, this review provides an overview of the current progress in the discovery and development of TOPK inhibitors, considering future clinical applications.
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http://dx.doi.org/10.3390/cancers13092232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124186PMC
May 2021

A Small Molecule Antagonist of PD-1/PD-L1 Interactions Acts as an Immune Checkpoint Inhibitor for NSCLC and Melanoma Immunotherapy.

Front Immunol 2021 14;12:654463. Epub 2021 May 14.

Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.

Immune checkpoint inhibitors, such as monoclonal antibodies targeting programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1), have achieved enormous success in the treatment of several cancers. However, monoclonal antibodies are expensive to produce, have poor tumor penetration, and may induce autoimmune side effects, all of which limit their application. Here, we demonstrate that PDI-1 (also name PD1/PD-L1 inhibitor 1), a small molecule antagonist of PD-1/PD-L1 interactions, shows potent anti-tumor activity and and acts by relieving PD-1/PD-L1-induced T cell exhaustion. We show that PDI-1 binds with high affinity to purified human and mouse PD-1 and PD-L1 proteins and is a competitive inhibitor of human PD-1/PD-L1 binding . Incubation of activated human T cells with PDI-1 enhanced their cytotoxicity towards human lung cancer and melanoma cells, and concomitantly increased the production of granzyme B, perforin, and inflammatory cytokines. Luciferase reporter assays showed that PDI-1 directly increases TCR-mediated activation of NFAT in a PD-1/PD-L1-dependent manner. In two syngeneic mouse tumor models, the intraperitoneal administration of PDI-1 reduced the growth of tumors derived from human PD-L1-transfected mouse lung cancer and melanoma cells; increased and decreased the abundance of tumor-infiltrating CD8+ and FoxP3+ CD4+ T cells, respectively; decreased the abundance of PD-L1-expressing tumor cells, and increased the production of inflammatory cytokines. The anti-tumor effect of PDI-1 was comparable to that of the anti-PD-L1 antibody atezolizumab. These results suggest that the small molecule inhibitors of PD-1/PD-L1 may be effective as an alternative or complementary immune checkpoint inhibitor to monoclonal antibodies.
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http://dx.doi.org/10.3389/fimmu.2021.654463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160380PMC
September 2021

Targeting LIMK1 with luteolin inhibits the growth of lung cancer in vitro and in vivo.

J Cell Mol Med 2021 06 13;25(12):5560-5571. Epub 2021 May 13.

China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.

Lung cancer is the leading cause of cancer-related deaths. LIM domain kinase (LIMK) 1 is a member of serine/threonine kinase family and highly expressed in various cancers. Luteolin, a polyphenolic plant flavonoid, has been reported to suppress tumour proliferation through inducing apoptosis and autophagy via MAPK activation in glioma. However, the mechanism of luteolin on suppressing lung cancer growth is still unclear. We found that luteolin targeted LIMK1 from the in silico screening and significantly inhibited the LIMK1 kinase activity, which was confirmed with pull-down binding assay and computational docking models. Treatment with luteolin inhibited lung cancer cells anchorage-independent colony growth and induced apoptosis and cell cycle arrest at G1 phase. Luteolin also decreased the expression of cyclin D1 and increased the levels of cleaved caspase-3 by down-regulating LIMK1 signalling related targets, including p-LIMK and p-cofilin. Furthermore, luteolin suppressed the lung cancer patient-derived xenograft tumour growth by decreasing Ki-67, p-LIMK and p-cofilin expression in vivo. Taken together, these results provide insight into the mechanism that underlies the anticancer effects of luteolin on lung cancer, which involved in down-regulation of LIMK1 and its interaction with cofilin. It also provides valuable evidence for translation towards lung cancer clinical trials with luteolin.
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http://dx.doi.org/10.1111/jcmm.16568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184676PMC
June 2021

Costunolide suppresses melanoma growth via the AKT/mTOR pathway and .

Am J Cancer Res 2021 15;11(4):1410-1427. Epub 2021 Apr 15.

Department of Animal Science and Biotechnology, Kyungpook National University Sangju-si, Gyeongsang buk-do 37224, Republic of Korea.

Melanoma is the most common type of skin cancer and its incidence is rapidly increasing. AKT, and its related signaling pathways, are highly activated in many cancers including lung, colon, and esophageal cancers. Costunolide (CTD) is a sesquiterpene lactone that has been reported to possess neuroprotective, anti-inflammatory, and anti-cancer properties. However, the target and mechanism underlying its efficacy in melanoma have not been identified. In this study, we elucidated the mechanism behind the anti-cancer effect of CTD in melanoma and by identifying CTD as an AKT inhibitor. We first verified that p-AKT and AKT are highly expressed in melanoma patient tissues and cell lines. CTD significantly inhibited the proliferation, migration, and invasion of melanoma cells including SK-MEL-5, SK-MEL-28, and A375 that are overexpressed p-AKT and AKT proteins. We investigated the mechanism of CTD using a computational docking modeling, pull-down, and site directed mutagenesis assay. CTD directly bound to AKT thereby arresting cell cycle at the G1 phase, and inducing the apoptosis of melanoma cells. In addition, CTD regulated the G1 phase and apoptosis biomarkers, and inhibited the expression of AKT/mTOR/GSK3b/p70S6K/4EBP cascade proteins. After reducing AKT expression in melanoma cells, cell growth was significantly decreased and CTD did not showed further inhibitory effects. Furthermore, CTD administration suppressed tumor growth and weight in cell-derived xenograft mice models without body weight loss and inhibited the expression of Ki-67, p-AKT, and p70S6K in tumor tissues. In summary, our study implied that CTD inhibited melanoma progression and . In this study, we reported that CTD could affect melanoma growth by targeting AKT. Therefore, CTD has considerable potential as a drug for melanoma therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085867PMC
April 2021

The 3-deoxysappanchalcone induces ROS-mediated apoptosis and cell cycle arrest via JNK/p38 MAPKs signaling pathway in human esophageal cancer cells.

Phytomedicine 2021 Jun 4;86:153564. Epub 2021 Apr 4.

Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea; The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, PR China; Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea. Electronic address:

Background: The 3-deoxysappanchalcone (3-DSC), a chemical separated from Caesalpinia sappan L, has been substantiated to display anti-inflammatory, anti-influenza, and anti-allergy activities according to previous studies. However, the underlying mechanisms of action on esophageal cancer remain unknown.

Purpose: The present research aims to survey the action mechanisms of 3-DSC in esophageal squamous cell carcinoma (ESCC) cells in vitro.

Methods: Evaluation of cytotoxicity was determined by MTT tetrazolium salt assay and soft agar assay. Cell cycle distribution, apoptosis induction, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), and multi-caspases activity were appreciated by Muse™ Cell Analyzer. The expressions of cell cycle- and apoptosis-related proteins were presented using Western blotting.

Results: 3-DSC blocked cell growth and colony formation ability in a concentration-dependent manner and invoked apoptosis, G2/M cell cycle arrest, ROS production, MMP depolarization, and multi-caspase activity. Furthermore, Western blotting results demonstrated that 3-DSC upregulated the expression of phospho (p)-c-jun NH2-terminal kinases (JNK), p-p38, cell cycle regulators, pro-apoptotic proteins, and endoplasmic reticulum (ER) stress-related proteins whereas downregulated the levels of anti-apoptotic proteins and cell cycle promoters. The effects of 3-DSC on ROS induction were counteracted by pretreatment with N-acetyl-L-cysteine (NAC). Also, our results indicated that p38 (SB203580) and JNK (SP600125) inhibitor slightly inhibited 3-DSC-induced apoptosis. These results showed that 3-DSC-related G2/M phase cell cycle arrest and apoptosis by JNK/p38 MAPK signaling pathway in ESCC cells were mediated by ROS.

Conclusion: ROS generation by 3-DSC in cancer cells could be an attractive strategy for apoptosis of cancer cells by inducing cell cycle arrest, ER stress, MMP loss, multi-caspase activity, and JNK/p38 MAPK pathway. Our findings suggest that 3-DSC is a promising novel therapeutic candidate for both prevention and treatment of esophageal cancer.
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http://dx.doi.org/10.1016/j.phymed.2021.153564DOI Listing
June 2021

3-Deoxysappanchalcone Inhibits Skin Cancer Proliferation by Regulating T-Lymphokine-Activated Killer Cell-Originated Protein Kinase and .

Front Cell Dev Biol 2021 25;9:638174. Epub 2021 Mar 25.

Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, China.

Background: Skin cancer is one of the most commonly diagnosed cancers worldwide. The 5-year survival rate of the most aggressive late-stage skin cancer ranges between 20 and 30%. Thus, the discovery and investigation of novel target therapeutic agents that can effectively treat skin cancer is of the utmost importance. The T-lymphokine-activated killer cell-originated protein kinase (TOPK), which belongs to the serine-threonine kinase class of the mitogen-activated protein kinase kinase (MAPKK) family, is highly expressed and activated in skin cancer. The present study investigates the role of 3-deoxysappanchalcone (3-DSC), a plant-derived functional TOPK inhibitor, in suppressing skin cancer cell growth.

Purpose: In the context of skin cancer prevention and therapy, we clarify the effect and mechanism of 3-DSC on different types of skin cancer and solar-simulated light (SSL)-induced skin hyperplasia.

Methods: In an study, western blotting and kinase assays were utilized to determine the protein expression of TOPK and its activity, respectively. Pull-down assay with 3-DSC and TOPK (wild-type and T42A/N172 mutation) was performed to confirm the direct interaction between T42A/N172 amino acid sites of TOPK and 3-DSC. Cell proliferation and anchorage-independent cell growth assays were utilized to determine the effect of 3-DSC on cell growth. In an study, the thickness of skin and tumor size were measured in the acute SSL-induced inflammation mouse model or SK-MEL-2 cell-derived xenografts mouse model treated with 3-DSC. Immunohistochemistry analysis of tumors isolated from SK-MEL-2 cell-derived xenografts was performed to determine whether cell-based results observed upon 3-DSC treatment could be recapitulated .

Results: 3-DSC is able to inhibit cell proliferation in skin cancer cells in an anchorage-dependent and anchorage-independent manner by regulation of TOPK and its related signaling pathway . We also found that application of 3-DSC reduced acute SSL-induced murine skin hyperplasia. Additionally, we observed that 3-DSC decreased SK-MEL-2 cell-derived xenograft tumor growth through attenuating phosphorylation of TOPK and its downstream effectors including ERK, RSK, and c-Jun.

Conclusions: Our results suggest that 3-DSC may function in a chemopreventive and chemotherapeutic capacity by protecting against UV-induced skin hyperplasia and inhibiting tumor cell growth by attenuating TOPK signaling, respectively.
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http://dx.doi.org/10.3389/fcell.2021.638174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027363PMC
March 2021

Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo.

J Exp Clin Cancer Res 2021 Mar 30;40(1):114. Epub 2021 Mar 30.

Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, Sangju, 37224, Republic of Korea.

Background: Colorectal cancer (CRC) is a clinically challenging malignant tumor worldwide. As a natural product and sesquiterpene lactone, Costunolide (CTD) has been reported to possess anticancer activities. However, the regulation mechanism and precise target of this substance remain undiscovered in CRC. In this study, we found that CTD inhibited CRC cell proliferation in vitro and in vivo by targeting AKT.

Methods: Effects of CTD on colon cancer cell growth in vitro were evaluated in cell proliferation assays, migration and invasion, propidium iodide, and annexin V-staining analyses. Targets of CTD were identified utilizing phosphoprotein-specific antibody array; Costunolide-sepharose conjugated bead pull-down analysis and knockdown techniques. We investigated the underlying mechanisms of CTD by ubiquitination, immunofluorescence staining, and western blot assays. Cell-derived tumour xenografts (CDX) in nude mice and immunohistochemistry were used to assess anti-tumour effects of CTD in vivo.

Results: CTD suppressed the proliferation, anchorage-independent colony growth and epithelial-mesenchymal transformation (EMT) of CRC cells including HCT-15, HCT-116 and DLD1. Besides, the CTD also triggered cell apoptosis and cell cycle arrest at the G2/M phase. The CTD activates and induces p53 stability by inhibiting MDM2 ubiquitination via the suppression of AKT's phosphorylation in vitro. The CTD suppresses cell growth in a p53-independent fashion manner; p53 activation may contribute to the anticancer activity of CTD via target AKT. Finally, the CTD decreased the volume of CDX tumors without of the body weight loss and reduced the expression of AKT-MDM2-p53 signaling pathway in xenograft tumors.

Conclusions: Our project has uncovered the mechanism underlying the biological activity of CTD in colon cancer and confirmed the AKT is a directly target of CTD. All of which These results revealed that CTD might be a new AKT inhibitor in colon cancer treatment, and CTD is worthy of further exploration in preclinical and clinical trials.
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http://dx.doi.org/10.1186/s13046-021-01895-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010944PMC
March 2021

Deoxypodophyllotoxin Inhibits Cell Growth and Induces Apoptosis by Blocking EGFR and MET in Gefitinib-Resistant Non-Small Cell Lung Cancer.

J Microbiol Biotechnol 2021 Apr;31(4):559-569

Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea.

As one of the major types of lung cancer, non-small cell lung cancer (NSCLC) accounts for the majority of cancer-related deaths worldwide. Treatments for NSCLC includes surgery, chemotherapy, and targeted therapy. Among the targeted therapies, resistance to inhibitors of the epidermal growth factor receptor (EGFR) is common and remains a problem to be solved. (hepatocyte growth factor receptor) amplification is one of the major causes of EGFR-tyrosine kinase inhibitor (TKI) resistance. Therefore, there exists a need to find new and more efficacious therapies. Deoxypodophyllotoxin (DPT) extracted from roots exhibits various pharmacological activities including anti-inflammation and anti-cancer effects. In this study we sought to determine the anti-cancer effects of DPT on HCC827GR cells, which are resistant to gefitinib (EGFR-TKI) due to regulation of EGFR and MET and their related signaling pathways. To identify the direct binding of DPT to EGFR and MET, we performed pull-down, ATP-binding, and kinase assays. DPT exhibited competitive binding with ATP against the network kinases EGFR and MET and reduced their activities. Also, DPT suppressed the expression of p-EGFR and p-MET as well as their downstreat proteins p-ErbB3, p-AKT, and p-ERK. The treatment of HCC827GR cells with DPT induced high ROS generation that led to endoplasmic-reticulum stress. Accordingly, loss of mitochondrial membrane potential and apoptosis by multi-caspase activation were observed. In conclusion, these results demonstrate the apoptotic effects of DPT on HCC827GR cells and signify the potential of DPT to serve as an adjuvant anti-cancer drug by simultaneously inhibiting EGFR and MET.
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http://dx.doi.org/10.4014/jmb.2101.01029DOI Listing
April 2021

Dasatinib Inhibits Lung Cancer Cell Growth and Patient Derived Tumor Growth in Mice by Targeting LIMK1.

Front Cell Dev Biol 2020 4;8:556532. Epub 2020 Dec 4.

China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.

Lung cancer is a leading cause cancer-related death with diversity. A promising approach to meet the need for improved cancer treatment is drug repurposing. Dasatinib, a second generation of tyrosine kinase inhibitors (TKIs), is a potent treatment agent for chronic myeloid leukemia (CML) approved by FDA, however, its off-targets and the underlying mechanisms in lung cancer have not been elucidated yet. LIM kinase 1 (LIMK1) is a serine/threonine kinase, which is highly upregulated in human cancers. Herein, we demonstrated that dasatinib dose-dependently blocked lung cancer cell proliferation and repressed LIMK1 activities by directly targeting LIMK1. It was confirmed that knockdown of LIMK1 expression suppressed lung cancer cell proliferation. From the screening results, dasatinib may target to LIMK1. Indeed, dasatinib significantly inhibited the LIMK1 activity as evidenced by kinase and binding assay, and computational docking model analysis. Dasatinib inhibited lung cancer cell growth, while induced cell apoptosis as well as cell cycle arrest at the G1 phase. Meanwhile, dasatinib also suppressed the expression of markers relating cell cycle, cyclin D1, D3, and CDK2, and increased the levels of markers involved in cell apoptosis, cleaved caspase-3 and caspase-7 by downregulating phosphorylated LIMK1 (p-LIMK1) and cofilin (p-cofilin). Furthermore, in patient-derived xenografts (PDXs), dasatinib (30 mg/kg) significantly inhibited the growth of tumors in SCID mice which highly expressed LIMK1 without changing the bodyweight. In summary, our results indicate that dasatinib acts as a novel LIMK1 inhibitor to suppress the lung cancer cell proliferation and tumor growth , which suggests evidence for the application of dasatinib in lung cancer therapy.
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http://dx.doi.org/10.3389/fcell.2020.556532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746816PMC
December 2020

Estrogen-related receptor alpha directly binds to p53 and cooperatively controls colon cancer growth through the regulation of mitochondrial biogenesis and function.

Cancer Metab 2020 Dec 10;8(1):28. Epub 2020 Dec 10.

Department of Pathophysiology, Zhengzhou University School of Medicine, 40 North Road, 27 District University, Zhengzhou, 450052, China.

Background: Of the genes that control mitochondrial biogenesis and function, ERRα emerges as a druggable metabolic target to be exploited for cancer therapy. Of the genes mutated in cancer, TP53 remains the most elusive to target. A clear understanding of how mitochondrial druggable targets can be accessed to exploit the underlying mechanism(s) explaining how p53-deficient tumors promote cell survival remains elusive.

Methods: We performed protein-protein interaction studies to demonstrate that ERRα binds to p53. Moreover, we used gene silencing and pharmacological approaches in tandem with quantitative proteomics analysis by SWATH-MS to investigate the role of the ERRα/p53 complex in mitochondrial biogenesis and function in colon cancer. Finally, we designed in vitro and in vivo studies to investigate the possibility of targeting colon cancers that exhibit defects in p53.

Results: Here, we are the first to identify a direct protein-protein interaction between the ligand-binding domain (LBD) of ERRα and the C-terminal domain (CTD) of p53. ERRα binds to p53 regardless of p53 mutational status. Furthermore, we show that the ERRα and p53 complex cooperatively control mitochondrial biogenesis and function. Targeting ERRα creates mitochondrial metabolic stresses, such as production of reactive oxygen species (ROS) and mitochondrial membrane permeabilization (MMP), leading to a greater cytotoxic effect that is dependent on the presence of p53. Pharmacological inhibition of ERRα impairs the growth of p53-deficient cells and of p53 mutant patient-derived colon xenografts (PDX).

Conclusions: Therefore, our data suggest that by using the status of the p53 protein as a selection criterion, the ERRα/p53 transcriptional axis can be exploited as a metabolic vulnerability.
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http://dx.doi.org/10.1186/s40170-020-00234-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731476PMC
December 2020

Targeted inhibition of c-MET by podophyllotoxin promotes caspase-dependent apoptosis and suppresses cell growth in gefitinib-resistant non-small cell lung cancer cells.

Phytomedicine 2021 Jan 25;80:153355. Epub 2020 Sep 25.

Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, P.R. China; Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea. Electronic address:

Background: Lung cancer has the highest incidence and cancer-related mortality of all cancers worldwide. Its treatment is focused on molecular targeted therapy. c-MET plays an important role in the development and metastasis of various human cancers and has been identified as an attractive potential anti-cancer target. Podophyllotoxin (PPT), an aryltetralin lignan isolated from the rhizomes of Podophyllum species, has several pharmacological activities that include anti-viral and anti-cancer effects. However, the mechanism of the anti-cancer effects of PPT on gefitinib-sensitive (HCC827) or -resistant (MET-amplified HCC827GR) non-small cell lung cancer (NSCLC) cells remains unexplored.

Purpose: In the present study, we investigated the underlying mechanisms of PPT-induced apoptosis in NSCLC cells and found that the inhibition of c-MET kinase activity contributed to PPT-induced cell death.

Methods: The regulation of c-MET by PPT was examined by pull-down assay, ATP-competitive binding assay, kinase activity assay, molecular docking simulation, and Western blot analysis. The cell growth inhibitory effects of PPT on NSCLC cells were assessed using the MTT assay, soft agar assay, and flow cytometry analysis.

Results: PPT could directly interact with c-MET and inhibit kinase activity, which further induced the apoptosis of HCC827GR cells. In contrast, PPT did not significantly affect EGFR kinase activity. PPT significantly inhibited the cell viability of HCC827GR cells, whereas the PPT-treated HCC827 cells showed a cell viability of more than 80%. PPT dose-dependently induced G2/M cell cycle arrest, as shown by the downregulation of cyclin B1 and cdc2, and upregulation of p27 expression in HCC827GR cells. Furthermore, PPT treatment induced Bad expression and downregulation of Mcl-1, survivin, and Bcl-xl expression, subsequently activating multi-caspases. PPT thereby induced caspase-dependent apoptosis in HCC827GR cells.

Conclusion: These results suggest the potential of PPT as a c-MET inhibitor to overcome tyrosine kinase inhibitor resistance in lung cancer.
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http://dx.doi.org/10.1016/j.phymed.2020.153355DOI Listing
January 2021

Alternative Options for Skin Cancer Therapy via Regulation of AKT and Related Signaling Pathways.

Int J Mol Sci 2020 Sep 18;21(18). Epub 2020 Sep 18.

Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Korea.

Global environmental pollution has led to human exposure to ultraviolet (UV) radiation due to the damaged ozone layer, thereby increasing the incidence and death rate of skin cancer including both melanoma and non-melanoma. Overexpression and activation of V-akt murine thymoma viral oncogene homolog (AKT, also known as protein kinase B) and related signaling pathways are major factors contributing to many cancers including lung cancer, esophageal squamous cell carcinoma and skin cancer. Although BRAF inhibitors are used to treat melanoma, further options are needed due to treatment resistance and poor efficacy. Depletion of AKT expression and activation, and related signaling cascades by its inhibitors, decreases the growth of skin cancer and metastasis. Here we have focused the effects of AKT and related signaling (PI3K/AKT/mTOR) pathways by regulators derived from plants and suggest the need for efficient treatment in skin cancer therapy.
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http://dx.doi.org/10.3390/ijms21186869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560163PMC
September 2020

Deoxypodophyllotoxin, a Lignan from , Induces Apoptosis and Cell Cycle Arrest by Inhibiting the EGFR Signaling Pathways in Esophageal Squamous Cell Carcinoma Cells.

Int J Mol Sci 2020 Sep 18;21(18). Epub 2020 Sep 18.

Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Korea.

Deoxypodophyllotoxin (DPT) derived from (L.) Hoffm has attracted considerable interest in recent years because of its anti-inflammatory, antitumor, and antiviral activity. However, the mechanisms underlying DPT mediated antitumor activity have yet to be fully elucidated in esophageal squamous cell carcinoma (ESCC). We show here that DPT inhibited the kinase activity of epidermal growth factor receptor (EGFR) directly, as well as phosphorylation of its downstream signaling kinases, AKT, GSK-3β, and ERK. We confirmed a direct interaction between DPT and EGFR by pull-down assay using DPT-beads. DPT treatment suppressed ESCC cell viability and colony formation in a time- and dose-dependent manner, as shown by MTT analysis and soft agar assay. DPT also down-regulated cyclin B1 and cdc2 expression to induce G2/M phase arrest of the cell cycle and upregulated p21 and p27 expression. DPT treatment of ESCC cells triggered the release of cytochrome c via loss of mitochondrial membrane potential, thereby inducing apoptosis by upregulation of related proteins. In addition, treatment of KYSE 30 and KYSE 450 cells with DPT increased endoplasmic reticulum stress, reactive oxygen species generation, and multi-caspase activation. Consequently, our results suggest that DPT has the potential to become a new anticancer therapeutic by inhibiting EGFR mediated AKT/ERK signaling pathway in ESCC.
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http://dx.doi.org/10.3390/ijms21186854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555783PMC
September 2020

Effects of Dimethyl Sulfoxide on the Pluripotency and Differentiation Capacity of Mouse Embryonic Stem Cells.

Cell Reprogram 2020 10 16;22(5):244-253. Epub 2020 Sep 16.

Department of Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Korea.

Mouse embryonic stem cells (mESCs) go through self-renewal in the existence of the cytokine leukemia inhibitory factor (LIF). LIF is added to the mouse stem cells culture medium, and its removal results in fast differentiation. Dimethyl sulfoxide (DMSO) is one of the most used solvents in drug test. We exposed 4-day mESC cultures to different concentrations of DMSO (0.1%, 0.5%, 1.0%, and 2.0%) to identify the safest dose exhibiting efficacy as a solvent. mESCs grown under general pluripotency conditions in the absence of LIF were treated with DMSO. In addition, as a control for differentiation, mESCs were grown in the absence of LIF. DMSO upregulated the mRNA expression level of pluripotency markers. Moreover, DMSO reduced the mRNA expression levels of ectodermal marker (β-tubulin3), mesodermal marker (Hand1), and endodermal markers (Foxa2 and Sox17) in mESCs. These results indicate that DMSO treatment enhances the pluripotency and disrupts the differentiation of mESCs. We also show that members of the Tet oncogene family are critical to inhibiting the differentiation and methylation of mESCs. DMSO is appropriate to sustain the pluripotency of mESCs in the absence of LIF, and that mESCs can be sustained in an undifferentiated state using DMSO. Therefore, DMSO may, in part, function as a substitute for LIF.
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http://dx.doi.org/10.1089/cell.2020.0006DOI Listing
October 2020

Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells.

Sci Adv 2020 Jul 31;6(31):eaay9131. Epub 2020 Jul 31.

Division of Bioengineering, Incheon National University, Incheon 22012, Republic of Korea.

Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.
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http://dx.doi.org/10.1126/sciadv.aay9131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399646PMC
July 2020

Picropodophyllotoxin, an Epimer of Podophyllotoxin, Causes Apoptosis of Human Esophageal Squamous Cell Carcinoma Cells Through ROS-Mediated JNK/P38 MAPK Pathways.

Int J Mol Sci 2020 Jun 30;21(13). Epub 2020 Jun 30.

Department of Dental Pharmacology, School of Dentistry and Institute of Oral Bioscience, BK21 Plus, Jeonbuk National University, Jeonju 54896, Korea.

Esophageal squamous cell carcinoma (ESCC), a major histologic type of esophageal cancer, is one of the frequent causes of cancer-related death worldwide. Picropodophyllotoxin (PPT) is the main component of root with antitumor activity via apoptosis-mediated mechanisms in several cancer cells. However, the underlying mechanism of the PPT effects in apoptosis induction in cancer remains ambiguous. Hence, in this study, we evaluate the anti-cancer effects of PPT in apoptotic signaling pathway-related mechanisms in ESCC cells. First, to verify the effect of PPT on ESCC cell viability, we employed an MTT assay. PPT inhibited the viability of ESCC cells in time- and dose-dependent manners. PPT induced G2/M phase cell cycle arrest and annexin V-stained cell apoptosis through the activation of the c-Jun N-terminal kinase (JNK)/p38 pathways. Furthermore, the treatment of KYSE 30 and KYSE 450 ESCC cells with PPT induced apoptosis involving the regulation of endoplasmic reticulum stress- and apoptosis-related proteins by reactive oxygen species (ROS) generation, the loss of mitochondrial membrane potential, and multi-caspase activation. In conclusion, our results indicate that the apoptotic effect of PPT on ESCC cells has the potential to become a new anti-cancer drug by increasing ROS levels and inducing the JNK/p38 signaling pathways.
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http://dx.doi.org/10.3390/ijms21134640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369713PMC
June 2020

Xanthohumol Inhibits the Growth of Keratin 18-Overexpressed Esophageal Squamous Cell Carcinoma and .

Front Cell Dev Biol 2020 19;8:366. Epub 2020 May 19.

Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.

Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related death worldwide. Xanthohumol is a prenylated flavonoid isolated from . Although xanthohumol has been reported to exert anti-obesity, hypoglycemic, anti-hyperlipidemia and anti-cancer activities, the mechanisms underlying its chemotherapeutic activity are yet to be elucidated. In the present study, we found that xanthohumol inhibited ESCC cell proliferation and by targeting keratin (KRT)-18. Xanthohumol suppressed the proliferation, foci formation, and anchorage-independent colony growth of KYSE30 cells. Using xanthohumol-sepharose conjugated bead pull-down and mass/mass analysis, we found that KRT18 is a novel target of xanthohumol in KYSE30 cells. KRT18 protein was highly expressed in patient ESCC tissues compared to adjunct tissues. Anti-proliferative activity of xanthohumol was abrogated or enhanced according to the knockdown or overexpression of KRT18 protein, respectively. Xanthohumol also induced apoptosis and cell cycle arrest at G1 phase which was associated with the modulation of expression of related makers including cyclin D1, cyclin D3, and cleaved-PARP, Bcl-2, cytochrome c and Bax. While xanthohumol attenuated KRT18 protein expression, it failed to cause any change in the KRT18 mRNA level. Furthermore, oral administration of xanthohumol decreased tumor volume and weight in patient-derived xenografts (PDXs) tumors having overexpressed KRT18. Overall these results suggest that xanthohumol acts as a KRT18 regulator to suppress the growth of ESCC.
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http://dx.doi.org/10.3389/fcell.2020.00366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248302PMC
May 2020

Suppression of the solar ultraviolet-induced skin carcinogenesis by TOPK inhibitor HI-TOPK-032.

Oncogene 2020 05 10;39(21):4170-4182. Epub 2020 Apr 10.

The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.

Nonmelanoma skin cancer (NMSC) such as cutaneous squamous cell carcinoma (cSCC) is caused by solar ultraviolet (SUV) exposure and is the most common cancer in the United States. T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase is activated by SUV irradiation and involved in skin carcinogenesis. Strategies with research focusing on the TOPK signaling pathway and targeted therapy in skin carcinogenesis may helpful for the discovery of additional treatments against skin cancer. In this study, we found that TOPK can directly bind to and phosphorylate c-Jun (as one of the core member of AP-1) at Ser63 and Ser73 after SSL exposure in a JNKs-independent manner. TOPK knocking down, or HI-TOPK-032 (TOPK specific inhibitor) attenuated colony formation and cell proliferation of skin cancer cells. Phosphorylated levels of c-Jun were overexpressed in human AK and cSCC compared with normal skin tissues, and HI-TOPK-032 inhibited the phosphorylation of c-Jun in SCC cell line in a dose-dependent manner. Furthermore, HI-TOPK-032 decreased SSL-induced AP-1 transactivation activity. Moreover, acute SSL-induced inflammation was attenuated by the topical application of HI-TOPK-032 in SKH1 hairless mice. Importantly, HI-TOPK-032 suppressed chronic SSL-induced skin carcinogenesis and c-Jun phosphorylation levels in SKH1 hairless mice. Our results demonstrate that TOPK can phosphorylate and activate c-Jun at Ser63 and Ser73 in the process of skin carcinogenesis and HI-TOPK-032 could be used as a potential chemopreventive drug against cSCC development.
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http://dx.doi.org/10.1038/s41388-020-1286-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313813PMC
May 2020

Targeting Opsin4/Melanopsin with a Novel Small Molecule Suppresses PKC/RAF/MEK/ERK Signaling and Inhibits Lung Adenocarcinoma Progression.

Mol Cancer Res 2020 07 8;18(7):1028-1038. Epub 2020 Apr 8.

The Hormel Institute, University of Minnesota, Austin, Minnesota.

The identification of oncogenic biomolecules as drug targets is an unmet need for the development of clinically effective novel anticancer therapies. In this study, we report for the first time that opsin 4/melanopsin (OPN4) plays a critical role in the pathogenesis of non-small cell lung cancer (NSCLC) and is a potential drug target. Our study has revealed that OPN4 is overexpressed in human lung cancer tissues and cells, and is inversely correlated with patient survival probability. Knocking down expression of OPN4 suppressed cells growth and induced apoptosis in lung cancer cells. We have also found that OPN4, a G protein-coupled receptor, interacted with Gα11 and triggered the PKC/BRAF/MEK/ERKs signaling pathway in lung adenocarcinoma cells. Genetic ablation of attenuated the multiplicity and the volume of urethane-induced lung tumors in mice. Importantly, our study provides the first report of AE 51310 (1-[(2,5-dichloro-4-methoxyphenyl)sulfonyl]-3-methylpiperidine) as a small-molecule inhibitor of OPN4, suppressed the anchorage-independent growth of lung cancer cells and the growth of patient-derived xenograft tumors in mice. IMPLICATIONS: Overall, this study unveils the role of OPN4 in NSCLC and suggests that targeting OPN4 with small molecules, such as AE 51310 would be interesting to develop novel anticancer therapies for lung adenocarcinoma.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1120DOI Listing
July 2020

Janus kinase 2 inhibition by Licochalcone B suppresses esophageal squamous cell carcinoma growth.

Phytother Res 2020 Aug 6;34(8):2032-2043. Epub 2020 Mar 6.

Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan-gun, Republic of Korea.

Esophageal cancer (EC) is one of the leading causes to cancer death in the worldwide and major population of EC is esophageal squamous cell carcinoma (ESCC). Still, ESCC-targeted therapy has not been covered yet. In the present study we have identified that Licochalcone B (Lico B) inhibited the ESCC growth by directly blocking the Janus kinase (JAK) 2 activity and its downstream signaling pathway. Lico B suppressed KYSE450 and KYSE510 ESCC cell growth, arrested cell cycle at G2/M phase and induced apoptosis. Direct target of Lico B was identified by kinase assay and verified with in vitro and ex vivo binding. Computational docking model predicted for Lico B interaction to ATP-binding pocket of JAK2. Furthermore, treatment of JAK2 clinical medicine AZD1480 to ESCC cells showed similar tendency with Lico B. Thus, JAK2 downstream signaling proteins phosphorylation of STAT3 at Y705 and S727 as well as STAT3 target protein Mcl-1 expression was decreased with treatment of Lico B. Our results suggest that Lico B inhibits ESCC cell growth, arrests cell cycle and induces apoptosis, revealing the underlying mechanism involved in JAK2/STAT3 signaling pathways after Lico B treatment. It might provide potential role of Lico B in the treatment of ESCC.
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http://dx.doi.org/10.1002/ptr.6661DOI Listing
August 2020

Licochalcone D Induces ROS-Dependent Apoptosis in Gefitinib-Sensitive or Resistant Lung Cancer Cells by Targeting EGFR and MET.

Biomolecules 2020 02 13;10(2). Epub 2020 Feb 13.

Department of Pharmacy, Mokpo National University, Jeonnam 58554, Korea.

Licochalcone D (LCD), a flavonoid isolated from a Chinese medicinal plant , has a variety of pharmacological activities. However, the anti-cancer effects of LCD on non-small cell lung cancer (NSCLC) have not been investigated yet. The amplification of (hepatocyte growth factor receptor) compensates for the inhibition of epidermal growth factor receptor (EGFR) activity due to tyrosine kinase inhibitor (TKI), leading to TKI resistance. Therefore, EGFR and MET can be attractive targets for lung cancer. We investigated the anti-proliferative and apoptotic effects of LCD in lung cancer cells HCC827 (gefitinib-sensitive) and HCC827GR (gefitinib-resistant) through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, pull-down/kinase assay, cell cycle analysis, Annexin-V/7-ADD staining, reactive oxygen species (ROS) assay, mitochondrial membrane potential (MMP) assay, multi-caspase assay, and Western blot analysis. The results showed that LCD inhibited phosphorylation and the kinase activity of EGFR and MET. In addition, the predicted pose of LCD was competitively located at the ATP binding site. LCD suppressed lung cancer cells growth by blocking cell cycle progression at the G2/M transition and inducing apoptosis. LCD also induced caspases activation and poly (ADP-ribose) polymerase (PARP) cleavage, thus displaying features of apoptotic signals. These results provide evidence that LCD has anti-tumor effects by inhibiting EGFR and MET activities and inducing ROS-dependent apoptosis in NSCLC, suggesting that LCD has the potential to treat lung cancer.
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http://dx.doi.org/10.3390/biom10020297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072161PMC
February 2020

Licochalcone C induces cell cycle G1 arrest and apoptosis in human esophageal squamous carcinoma cells by activation of the ROS/MAPK signaling pathway.

J Chemother 2020 May 3;32(3):132-143. Epub 2020 Feb 3.

Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam, Republic of Korea.

Along with changes in dietary habits and lifestyle, the incidence of esophageal cancer is increasing around the world. Since chemotherapy for esophageal cancer has significant side effects, phytochemicals have attracted attention as an alternative medicine. Licochalcone C (LCC) is a flavonoid compound extracted from Licorice, with a variety of clinical uses including anti-cancer, anti-inflammatory and anti-oxidant effects. Treatment with LCC for 48 h significantly decreased cell viability of esophageal squamous cell carcinoma (ESCC) cells in a dose- and time-dependent manner with IC values of 28 µM (KYSE 30), 36 µM (KYSE 70), 19 µM (KYSE 410), 28 µM (KYSE 450) and 26 µM (KYSE 510). LCC induced G1 arrest accompanied by decreased cyclin D1 expression and an increase in the levels of p21 and p27. LCC increased the levels of intracellular ROS, cytochrome C release, and multi-caspase activity, and decreased mitochondrial membrane potential. LCC induced the protein expression of ER stress markers (GRP78 and CHOP) and phosphorylation JNK, c-Jun and p38. We investigated the expression of pro-apoptotic and anti-apoptotic proteins to elucidate the mechanism of apoptosis. Our findings contribute to the understanding of apoptosis mechanism underlying LCC in ESCC cells and provide new insights into the potential clinical opportunities of LCC for ESCC treatment.
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http://dx.doi.org/10.1080/1120009X.2020.1721175DOI Listing
May 2020

Acetylshikonin suppressed growth of colorectal tumour tissue and cells by inhibiting the intracellular kinase, T-lymphokine-activated killer cell-originated protein kinase.

Br J Pharmacol 2020 05 10;177(10):2303-2319. Epub 2020 Apr 10.

Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.

Background And Purpose: Overexpression or aberrant activation of the T-lymphokine-activated killer cell-originated protein kinase (TOPK) promotes gene expression and growth of solid tumours, implying that TOPK would be a rational target in developing novel anticancer drugs. Acetylshikonin, a diterpenoid compound isolated from Lithospermum erythrorhizon root, exerts a range of biological activities. Here we have investigated whether acetylshikonin, by acting as an inhibitor of TOPK, can attenuate the proliferation of colorectal cancer cells and the growth of patient-derived tumours, in vitro and in vivo.

Experimental Approach: Targets of acetylshikonin, were identified using kinase profiling analysis, kinetic/binding assay, and computational docking analysis and knock-down techniques. Effects of acetylshikonin on colorectal cancer growth and the underlying mechanisms were evaluated in cell proliferation assays, propidium iodide and annexin-V staining analyses and western blots. Patient-derived tumour xenografts in mice (PDX) and immunohistochemistry were used to assess anti-tumour effects of acetylshikonin.

Key Results: Acetylshikonin directly inhibited TOPK activity, interacting with the ATP-binding pocket of TOPK. Acetylshikonin suppressed cell proliferation by inducing cell cycle arrest at the G1 phase, stimulated apoptosis, and increased the expression of apoptotic biomarkers in colorectal cancer cell lines. Mechanistically, acetylshikonin diminished the phosphorylation and activation of TOPK signalling. Furthermore, acetylshikonin decreased the volume of PDX tumours and reduced the expression of TOPK signalling pathway in xenograft tumours.

Conclusion And Implications: Acetylshikonin suppressed growth of colorectal cancer cells by attenuating TOPK signalling. Targeted inhibition of TOPK by acetylshikonin might be a promising new approach to the treatment of colorectal cancer.
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http://dx.doi.org/10.1111/bph.14981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174886PMC
May 2020

(S)-10-Hydroxycamptothecin Inhibits Esophageal Squamous Cell Carcinoma Growth In Vitro and In Vivo Via Decreasing Topoisomerase I Enzyme Activity.

Cancers (Basel) 2019 Dec 6;11(12). Epub 2019 Dec 6.

Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.

Topoisomerase (TOP) I plays a major role in the process of supercoiled DNA relaxation, thereby facilitating DNA replication and cell cycle progression. The expression and enzymatic activity of TOP I is positively correlated with tumor progression. Although the anticancer activity of (S)-10-Hydroxycamptothecin (HCPT), a TOP I specific inhibitor, has been reported in various cancers, the effect of HCPT on esophageal cancer is yet to be examined. In this study, we investigate the potential of HCPT to inhibit the growth of ESCC cells in vitro and verify its anti-tumor activity in vivo by using a patient-derived xenograft (PDX) tumor model in mice. Our study revealed the overexpression of TOP I in ESCC cells and treatment with HCPT inhibited TOP I enzymatic activity at 24 h and decreased expression at 48 h and 72 h. HCPT also induced DNA damage by increasing the expression of H2A.X. HCPT significantly decreased the proliferation and anchorage-independent growth of ESCC cells (KYSE410, KYSE510, KYSE30, and KYSE450). Mechanistically, HCPT inhibited the G2/M phase cell cycle transition, decreased the expression of cyclin B1, and elevated p21 expression. In addition, HCPT stimulated ESCC cells apoptosis, which was associated with elevated expression of cleaved PARP, cleaved caspase-3, cleaved caspase-7, Bax, Bim, and inhibition of Bcl-2 expression. HCPT dramatically suppressed PDX tumor growth and decreased the expression of Ki-67 and TOP I and increased the level of cleaved caspase-3 and H2A.X expression. Taken together, our data suggested that HCPT inhibited ESCC growth, arrested cell cycle progression, and induced apoptosis both in vitro and in vivo via decreasing the expression and activity of TOP I enzyme.
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http://dx.doi.org/10.3390/cancers11121964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966462PMC
December 2019
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