Publications by authors named "Ann M Bode"

311 Publications

Conformational change of adenine nucleotide translocase-1 mediates cisplatin resistance induced by EBV-LMP1.

EMBO Mol Med 2021 Nov 9:e14072. Epub 2021 Nov 9.

Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.

Adenine nucleotide translocase-1 (ANT1) is an ADP/ATP transporter protein located in the inner mitochondrial membrane. ANT1 is involved not only in the processes of ADP/ATP exchange but also in the composition of the mitochondrial membrane permeability transition pore (mPTP); and the function of ANT1 is closely related to its own conformational changes. Notably, various viral proteins can interact directly with ANT1 to influence mitochondrial membrane potential by regulating the opening of mPTP, thereby affecting tumor cell fate. The Epstein-Barr virus (EBV) encodes the key tumorigenic protein, latent membrane protein 1 (LMP1), which plays a pivotal role in promoting therapeutic resistance in related tumors. In our study, we identified a novel mechanism for EBV-LMP1-induced alteration of ANT1 conformation in cisplatin resistance in nasopharyngeal carcinoma. Here, we found that EBV-LMP1 localizes to the inner mitochondrial membrane and inhibits the opening of mPTP by binding to ANT1, thereby favoring tumor cell survival and drug resistance. The ANT1 conformational inhibitor carboxyatractyloside (CATR) in combination with cisplatin improved the chemosensitivity of EBV-LMP1-positive cells. This finding confirms that ANT1 is a novel therapeutic target for overcoming cisplatin resistance in the future.
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http://dx.doi.org/10.15252/emmm.202114072DOI Listing
November 2021

ACSL family: The regulatory mechanisms and therapeutic implications in cancer.

Eur J Pharmacol 2021 Oct 29;909:174397. Epub 2021 Jul 29.

Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, Hunan, 410078, China; Molecular Imaging Research Center of Central South University, Changsha, Hunan, 410078, China. Electronic address:

Accumulating evidence shows that deregulation of fatty acid (FA) metabolism is associated with the development of cancer. Long-chain acyl-coenzyme A synthases (ACSLs) are responsible for activating long-chain FAs and are frequently deregulated in cancers. Among the five mammalian ACSL family members, ACSL1 is involved in the TNFα-mediated pro-inflammatory phenotype and mainly facilitates cancer progression. ACSL3 is an androgen-responsive gene. High ACSL3 expression has been detected in a variety of cancers, including melanoma, triple-negative breast cancer (TNBC) and high-grade non-small cell lung carcinoma (NSCLC), and correlates with worse prognosis of patients with these diseases. ACSL4 can exert opposing roles acting as a tumor suppressor or as an oncogene depending on the specific cancer type and tissue environment. Moreover, ACSL4 behaves as a crucial regulator in ferroptosis that is defined as a cell death process caused by iron-dependent peroxidation of lipids. ACSL5 is nuclear-coded and expressed in the mitochondria and physiologically participates in the pro-apoptotic sensing of cells. ACSL5 mainly acts as a tumor suppressor in cancers. ACSL6 downregulation has been observed in many forms of cancers, except in colorectal cancer (CRC). Here, we address the differential regulatory mechanisms of the ACSL family members as well as their functions in carcinogenesis. Moreover, we enumerate the clinical therapeutic implications of ACSLs, which might serve as valuable biomarkers and therapeutic targets for precision cancer treatment.
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http://dx.doi.org/10.1016/j.ejphar.2021.174397DOI Listing
October 2021

Roles of regulator of chromosome condensation 2 in cancer: Beyond its regulatory function in cell cycle.

Oncol Rev 2021 Feb 19;15(1):525. Epub 2021 Mar 19.

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

Regulator of chromosome condensation 2 (RCC2) is an essential protein in order for mitosis to proceed properly. It localizes in the centrosome of chromosomes where is involved in chromosome segregation and cytokinesis. Furthermore, RCC2 associates with integrin networks at the plasma membrane where participates in the control of cell movement. Because of its known role in cell cycle, RCC2 has been linked with cancer progression. Several reports show that RCC2 induces cancer hallmarks, but the mechanisms explaining how RCC2 exerts these roles are widely unknown. Here, we aim to summarize the main findings explaining the roles and mechanisms of RCC2 in cancer promotion. RCC2 is overexpressed in different cancers, including glioblastoma, lung, ovarian, and esophageal which is related to proliferation, migration, invasion promotion and tumor progression and metastasis . Besides, RCC2 overexpression induces epithelial-mesenchymal transition and causes poorer prognosis in cancer patients. RCC2 overexpression has also been linked with resistance development to chemotherapy and radiotherapy by inhibiting apoptosis and activating cancer-promoting transcription factors. Unfortunately, not RCC2 inhibitors are currently available for further pre-clinical and clinical assays. Therefore, these findings emphasize the potential use of RCC2 as a targetable biomarker in cancer and highlight the importance for designing RCC2 chemical inhibitors to evaluate its efficacy in animal studies and clinical trials.
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http://dx.doi.org/10.4081/oncol.2021.525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018209PMC
February 2021

Stabilization of p18 by deubiquitylase CYLD is pivotal for cell cycle progression and viral replication.

NPJ Precis Oncol 2021 Mar 2;5(1):14. Epub 2021 Mar 2.

Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.

p18 is a key negative regulator of cell cycle progression and mediates cell cycle arrest at the G1/S phase. Ubiquitination is the prime mechanism in regulating p18 protein abundance. However, so far no post- translational regulator, especially DUBs, has been identified to regulate the protein stability of p18. In this paper, we identified CYLD as a deubiquitinase of p18, which binds to and removes the K48-linked polyubiquitylation chains conjugated onto p18, thus stabilizing the p18 protein. Loss of CYLD causes the degradation of p18 and induces the G1/S transition. Epstein-Barr virus (EBV), is the human oncovirus etiologically linked to nasopharyngeal carcinoma (NPC). Here we found that EBV drives a replication passive environment by deregulating the CYLD-p18 axis. Functionally, CYLD inhibits cell proliferation and tumorigenesis through p18 in vivo. Restoring CYLD prevents EBV induced viral replication and tumor growth. Collectively, our results identify CYLD directly stabilizes p18 to regulate the cellular G1/S transition. The reconstitution of CYLD-p18 axis could be a promising approach for EBV-positive cancer therapy.
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http://dx.doi.org/10.1038/s41698-021-00153-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925679PMC
March 2021

()-Epigallocatechin-3-Gallate Inhibits EBV Lytic Replication via Targeting LMP1-Mediated MAPK Signal Axes.

Oncol Res 2021 Sep 17;28(7):763-778. Epub 2021 Feb 17.

Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South UniversityChangshaP.R. China.

EpsteinBarr virus (EBV)-encoded latent membrane protein 1 (LMP1) plays an important oncogenic role in the viral latent infection. Recently, increasing evidence indicates that the high expression of LMP1 during EBV lytic cycle is related to the viral lytic replication. However, the mechanism by which LMP1 regulates EBV lytic replication remains unclear. ()-Epigallocatechin-3-gallate (EGCG) prevents carcinogenesis by directly targeting numerous membrane proteins and effectively inhibits EBV lytic cascade. Here, we demonstrated that LMP1 promotes EBV lytic replication through the downstream signal molecules MAPKs, including ERKs, p38, and JNKs. LMP1 induces the phosphorylation of p53 through MAPKs to enhance the ability of wild-type p53 (wt-p53) to activate expression of BZLF1 gene, while the JNKs/c-Jun signal axis appears to be involved in EBV lytic replication induced by LMP1 in p53 mutant manner. We provided the first evidence that EGCG directly targets the viral membrane LMP1 ( =0.36 M, =1) using fluorescence quenching, isothermal titration calorimetry (ITC) assay, and CNBR-activated Sepharose 4B pull-down affinity chromatography. Furthermore, we revealed that EGCG inhibits EBV lytic replication via suppressing LMP1 and thus blocking the downstream MAPKs/wt-p53 signal axis in AGS-EBV cells and JNKs/c-Jun signal axis in p53 mutant B95.8 cells. Our study, for the first time, reports the binding and inhibitory efficacy of EGCG to the LMP1, which is a key oncoprotein encoded by EBV. These findings suggest the novel function of LMP1 in the regulation of EBV lytic cycle and reveal the new role of EGCG in EBV-associated malignancies through suppressing viral reactivation.
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http://dx.doi.org/10.3727/096504021X16135618512563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420900PMC
September 2021

Crystal structure of the human PRPK-TPRKB complex.

Commun Biol 2021 02 5;4(1):167. Epub 2021 Feb 5.

College of Medicine, Zhengzhou University, Zhengzhou, China.

Mutations of the p53-related protein kinase (PRPK) and TP53RK-binding protein (TPRKB) cause Galloway-Mowat syndrome (GAMOS) and are found in various human cancers. We have previously shown that small compounds targeting PRPK showed anti-cancer activity against colon and skin cancer. Here we present the 2.53 Å crystal structure of the human PRPK-TPRKB-AMPPNP (adenylyl-imidodiphosphate) complex. The structure reveals details in PRPK-AMPPNP coordination and PRPK-TPRKB interaction. PRPK appears in an active conformation, albeit lacking the conventional kinase activation loop. We constructed a structural model of the human EKC/KEOPS complex, composed of PRPK, TPRKB, OSGEP, LAGE3, and GON7. Disease mutations in PRPK and TPRKB are mapped into the structure, and we show that one mutation, PRPK K238Nfs*2, lost the binding to OSGEP. Our structure also makes the virtual screening possible and paves the way for more rational drug design.
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http://dx.doi.org/10.1038/s42003-021-01683-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864929PMC
February 2021

Targeting the signaling in Epstein-Barr virus-associated diseases: mechanism, regulation, and clinical study.

Signal Transduct Target Ther 2021 01 12;6(1):15. Epub 2021 Jan 12.

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

Epstein-Barr virus-associated diseases are important global health concerns. As a group I carcinogen, EBV accounts for 1.5% of human malignances, including both epithelial- and lymphatic-originated tumors. Moreover, EBV plays an etiological and pathogenic role in a number of non-neoplastic diseases, and is even involved in multiple autoimmune diseases (SADs). In this review, we summarize and discuss some recent exciting discoveries in EBV research area, which including DNA methylation alterations, metabolic reprogramming, the changes of mitochondria and ubiquitin-proteasome system (UPS), oxidative stress and EBV lytic reactivation, variations in non-coding RNA (ncRNA), radiochemotherapy and immunotherapy. Understanding and learning from this advancement will further confirm the far-reaching and future value of therapeutic strategies in EBV-associated diseases.
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http://dx.doi.org/10.1038/s41392-020-00376-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801793PMC
January 2021

Structural basis for multifunctional roles of human Ints3 C-terminal domain.

J Biol Chem 2021 Jan-Jun;296:100112. Epub 2020 Dec 3.

China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China; College of Medicine, Zhengzhou University, Zhengzhou, Henan, China. Electronic address:

Proper repair of damaged DNA is critical for the maintenance of genome stability. A complex composed of Integrator subunit 3 (Ints3), single-stranded DNA-binding protein 1 (SSB1), and SSB-interacting protein 1 (SSBIP1) is required for efficient homologous recombination-dependent repair of double-strand breaks (DSBs) and ataxia-telangiectasia mutated (ATM)-dependent signaling pathways. It is known that in this complex the Ints3 N-terminal domain scaffolds SSB1 and SSBIP1. However, the molecular basis for the function of the Ints3 C-terminal domain remains unclear. Here, we present the crystal structure of the Ints3 C-terminal domain, uncovering a HEAT-repeat superhelical fold. Using structure and mutation analysis, we show that the C-terminal domain exists as a stable dimer. A basic groove and a cluster of conserved residues on two opposite sides of the dimer bind single-stranded RNA/DNA (ssRNA/ssDNA) and Integrator complex subunit 6 (Ints6), respectively. Dimerization is required for nucleic acid binding, but not for Ints6 binding. Additionally, in vitro experiments using HEK 293T cells demonstrate that Ints6 interaction is critical for maintaining SSB1 protein level. Taken together, our findings establish the structural basis of a multifunctional Ints3 C-terminal module, allowing us to propose a novel mode of nucleic acid recognition by helical repeat protein and paving the way for future mechanistic studies.
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http://dx.doi.org/10.1074/jbc.RA120.016393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948952PMC
August 2021

ANTs and cancer: Emerging pathogenesis, mechanisms, and perspectives.

Biochim Biophys Acta Rev Cancer 2021 01 11;1875(1):188485. Epub 2020 Dec 11.

Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha 410078, China; Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, China; Molecular Imaging Research Center of Central South University, Changsha 410008, Hunan, China; Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, Changsha 410078, China; National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha 410078, China. Electronic address:

Adenine nucleotide translocases (ANTs) are a class of transporters located in the inner mitochondrial membrane that not only couple processes of cellular productivity and energy expenditure, but are also involved in the composition of the mitochondrial membrane permeability transition pore (mPTP). The function of ANTs has been found to be most closely related to their own conformational changes. Notably, as multifunctional proteins, ANTs play a key role in oncogenesis, which provides building blocks for tumor anabolism, control oxidative phosphorylation and glycolysis homeostasis, and govern cell death. Thus, ANTs constitute promising targets for the development of novel anticancer agents. Here, we review the recent findings regarding ANTs and their important mechanisms in cancer, with a focus on the therapeutic potential of targeting ANTs for cancer therapy.
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http://dx.doi.org/10.1016/j.bbcan.2020.188485DOI Listing
January 2021

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

Targeting Epstein-Barr virus oncoprotein LMP1-mediated high oxidative stress suppresses EBV lytic reactivation and sensitizes tumors to radiation therapy.

Theranostics 2020 25;10(26):11921-11937. Epub 2020 Oct 25.

Key Laboratory of Cancer Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, China.

Generating oxidative stress is a critical mechanism by which host cells defend against infection by pathogenic microorganisms. Radiation resistance is a critical problem in radiotherapy against cancer. Epstein-Barr virus (EBV) is a cancer-causing virus and its reactivation plays an important role in the development of EBV-related tumors. This study aimed to explore the inner relationship and regulatory mechanism among oxidative stress, EBV reactivation, and radioresistance and to identify new molecular subtyping models and treatment strategies to improve the therapeutic effects of radiotherapy. ROS, NADP/NADPH, and GSSG/GSH were detected to evaluate the oxidative stress of cells. 8-OHdG is a reliable oxidative stress marker to evaluate the oxidative stress in patients. Its concentration in serum was detected using an ELISA method and in biopsies was detected using IHC. qPCR array was performed to evaluate the expression of essential oxidative stress genes. qPCR, Western blot, and IHC were used to measure the level of EBV reactivation and . A Rta-IgG ELISA kit and EBV DNA detection kit were used to analyze the reactivation of EBV in serum from NPC patients. NPC tumor tissue microarrays was used to investigate the prognostic role of oxidative stress and EBV reactivation. Radiation resistance was evaluated by a colony formation assay. Xenografts were treated with NAC, radiation, or a combination of NAC and radiation. EBV DNA load of tumor tissue was evaluated using an EBV DNA detection kit. Oxidative stress, EBV reactivation, and the apoptosis rate in tumor tissues were detected by using 8-OHdG, EAD, and TUNEL assays, respectively. We found that EBV can induce high oxidative stress, which promotes its reactivation and thus leads to radioresistance. Basically, EBV caused NPC cells to undergo a process of 'Redox Resetting' to acquire a new redox status with higher levels of ROS accumulation and stronger antioxidant systems by increasing the expression of the ROS-producing enzyme, NOX2, and the cellular master antioxidant regulator, Nrf2. Also, EBV encoded driving protein LMP1 promotes EBV reactivation through production of ROS. Furthermore, high oxidative stress and EBV reactivation were positively associated with poor overall survival of patients following radiation therapy and were significant related to NPC patients' recurrence and clinical stage. By decreasing oxidative stress using an FDA approved antioxidant drug, NAC, sensitivity of tumors to radiation was increased. Additionally, 8-OHdG and EBV DNA could be dual prognostic markers for NPC patients. Oxidative stress mediates EBV reactivation and leads to radioresistance. Targeting oxidative stress can provide therapeutic benefits to cancer patients with radiation resistance. Clinically, we, for the first time, generated a molecular subtyping model for NPC relying on 8-OHdG and EBV DNA level. These dual markers could identify patients who are at a high risk of poor outcomes but who might benefit from the sequential therapy of reactive oxygen blockade followed by radiation therapy, which provides novel perspectives for the precise treatment of NPC.
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http://dx.doi.org/10.7150/thno.46006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667690PMC
June 2021

GSK3β-Mediated Expression of CUG-Translated WT1 Is Critical for Tumor Progression.

Cancer Res 2021 02 12;81(4):945-955. Epub 2020 Nov 12.

College of Medicine, Zhengzhou University, Henan, China.

The () gene is well known as a chameleon gene. It plays a role as a tumor suppressor in Wilms' tumor but also acts as an oncogene in other cancers. Previously, our group reported that a canonical AUG starting site for the WT1 protein (augWT1) acts as a tumor suppressor, whereas a CUG starting site for the WT1 protein (cugWT1) functions as an oncogene. In this study, we report an oncogenic role of cugWT1 in the AOM/DSS-induced colon cancer mouse model and in a urethane-induced lung cancer model in mice lacking cugWT1. Development of chemically-induced tumors was significantly depressed in cugWT1-deficient mice. Moreover, glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box WD repeat-containing protein 8. Overall, our findings suggest that inhibition of cugWT1 expression provides a potential candidate target for therapy. SIGNIFICANCE: These findings demonstrate that CUG-translated WT1 plays an oncogenic role , and GSK3β-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1880DOI Listing
February 2021

HI-511 overcomes melanoma drug resistance targeting AURKB and BRAF V600E.

Theranostics 2020 1;10(21):9721-9740. Epub 2020 Aug 1.

The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA.

Melanoma is an aggressive tumor of the skin and drug resistance is still a major problem in melanoma therapy. Novel targets and effective agents to overcome drug resistant melanoma are urgently needed in clinical therapy. Gene Expression Omnibus (GEO) database analysis, pathway enrichment analysis, and survival rate analysis were utilized to identify a candidate target. An anchorage-independent cell growth assay, flow cytometry, Western blot, and a xenograft mouse model were used to study the function of Aurora kinase B (AURKB) in both drug-sensitive and drug-resistant melanoma. Next, HI-511, a novel dual-target inhibitor targeting both AURKB and BRAF V600E, was designed and examined by an kinase assay. Methods as indicated above in addition to a BRAF V600E/PTEN-loss melanoma mouse model were used to demonstrate the effect of HI-511 on melanoma development and . AURKB is highly expressed in melanoma and especially in vemurafenib-resistant melanoma and the expression was correlated with patient survival rate. Knocking down inhibited cell growth and induced apoptosis in melanoma, which was associated with the BRAF/MEK/ERKs and PI3-K/AKT signaling pathways. Importantly, we found that HI-511, a novel dual-target inhibitor against AURKB and BRAF V600E, suppresses both vemurafenib-sensitive and vemurafenib-resistant melanoma growth and by inducing apoptosis and mediating the inhibition of the BRAF/MEK/ERKs and PI3K/AKT signaling pathways. AURKB is a potential target for melanoma treatment. HI-511, a novel dual-target inhibitor against both AURKB and BRAF V600E, could achieve durable suppression of melanoma growth, even drug-resistant melanoma growth.
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http://dx.doi.org/10.7150/thno.44342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449901PMC
May 2021

ARC Is a Critical Protector against Inflammatory Bowel Disease (IBD) and IBD-Associated Colorectal Tumorigenesis.

Cancer Res 2020 10 19;80(19):4158-4171. Epub 2020 Aug 19.

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

The key functional molecules involved in inflammatory bowel disease (IBD) and IBD-induced colorectal tumorigenesis remain unclear. In this study, we found that the apoptosis repressor with caspase recruitment domain (ARC) protein plays critical roles in IBD. ARC-deficient mice exhibited substantially higher susceptibility to dextran sulfate sodium (DSS)-induced IBD compared with wild-type mice. The inflammatory burden induced in ARC-deficient conditions was inversely correlated with CCL5 and CXCL5 levels in immune cells, especially CD4-positive T cells. Pathologically, ARC expression in immune cells was significantly decreased in clinical biopsy specimens from patients with IBD compared with normal subjects. In addition, ARC levels inversely correlated with CCL5 and CXCL5 levels in human biopsy specimens. ARC interacted with TNF receptor associated factor (TRAF) 6, regulating ubiquitination of TRAF6, which was associated with NF-κB signaling. Importantly, we identified a novel ubiquitination site at lysine 461, which was critical in the function of ARC in IBD. ARC played a critical role in IBD and IBD-associated colon cancer in a bone marrow transplantation model and azoxymethane/DSS-induced colitis cancer mouse models. Overall, these findings reveal that ARC is critically involved in the maintenance of intestinal homeostasis and protection against IBD through its ubiquitination of TRAF6 and subsequent modulation of NF-κB activation in T cells. SIGNIFICANCE: This study uncovers a crucial role of ARC in the immune system and IBD, giving rise to a novel strategy for IBD and IBD-associated colon cancer therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0469DOI Listing
October 2020

RCC2 Promotes Esophageal Cancer Growth by Regulating Activity and Expression of the Sox2 Transcription Factor.

Mol Cancer Res 2020 11 14;18(11):1660-1674. Epub 2020 Aug 14.

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

Regulator of chromosome condensation 2 (RCC2) is a protein located in the centrosome, which ensures that cell division proceeds properly. Previous reports show that RCC2 is overexpressed in some cancers and could play a key role in tumor development, but the mechanisms concerning how this occurs are not understood. Furthermore, no evidence exists regarding its role in esophageal cancer. We studied the relevance of RCC2 in esophageal cancer growth and its regulation on Sox2, an important transcription factor promoting esophageal cancer. RCC2 was overexpressed in esophageal tumors compared with normal tissue, and this overexpression was associated with tumorigenicity by increasing cell proliferation, anchorage-independent growth, and migration. These oncogenic effects were accompanied by overexpression of Sox2. RCC2 upregulated and stabilized Sox2 expression and its target genes by inhibiting ubiquitination-mediated proteasome degradation. Likewise, RCC2 increased the transcriptional activity and promoter binding of Sox2. studies indicated that RCC2 and Sox2 were overexpressed in esophageal tumors compared with normal tissue, and this upregulation occurs in the esophageal basal cell layer for both proteins. In conditional knockout mice, RCC2 deletion decreased the tumor nodule formation and progression in the esophagus compared with wild-type mice. Proliferating cell nuclear antigen expression, a cell proliferation marker, was also downregulated in knockout mice. Overall, our data show for the first time that RCC2 is an important protein for the stabilization and transcriptional activation of Sox2 and further promotion of malignancy in esophageal cancer. IMPLICATIONS: This study shows that RCC2 controls Sox2 expression and transcriptional activity to mediate esophageal cancer formation.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1152DOI Listing
November 2020

Are FDA-Approved Sunscreen Components Effective in Preventing Solar UV-Induced Skin Cancer?

Cells 2020 07 11;9(7). Epub 2020 Jul 11.

The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.

Solar ultraviolet (SUV) exposure is a major risk factor in the etiology of cutaneous squamous cell carcinoma (cSCC). People commonly use sunscreens to prevent SUV-induced skin damage and cancer. Nonetheless, the prevalence of cSCC continues to increase every year, suggesting that commercially available sunscreens might not be used appropriately or are not completely effective. In the current study, a solar simulated light (SSL)-induced cSCC mouse model was used to investigate the efficacy of eight commonly used FDA-approved sunscreen components against skin carcinogenesis. First, we tested FDA-approved sunscreen components for their ability to block UVA or UVB irradiation by using VITRO-SKIN (a model that mimics human skin properties), and then the efficacy of FDA-approved sunscreen components was investigated in an SSL-induced cSCC mouse model. Our results identified which FDA-approved sunscreen components or combinations are effective in preventing cSCC development. Not surprisingly, the results indicated that sunscreen combinations that block both UVA and UVB significantly suppressed the formation of cutaneous papillomas and cSCC development and decreased the activation of oncoproteins and the expression of COX-2, keratin 17, and EGFR in SSL-exposed SKH-1 (Crl:SKH1-) hairless mouse skin. Notably, several sunscreen components that were individually purported to block both UVA and UVB were ineffective alone. At least one component had toxic effects that led to a high mortality rate in mice exposed to SSL. Our findings provide new insights into the development of the best sunscreen to prevent chronic SUV-induced cSCC development.
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http://dx.doi.org/10.3390/cells9071674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407267PMC
July 2020

Knock-down of the TIM/TIPIN complex promotes apoptosis in melanoma cells.

Oncotarget 2020 May 19;11(20):1846-1861. Epub 2020 May 19.

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

The Timeless (TIM) and it's interacting partner TIPIN protein complex is well known for its role in replication checkpoints and normal DNA replication processes. Recent studies revealed the involvement of TIM and TIPIN in human malignancies; however, no evidence is available regarding the expression of the TIM/TIPIN protein complex or its potential role in melanoma. Therefore, we investigated the role of this complex in melanoma. To assess the role of the TIM/TIPIN complex in melanoma, we analyzed TIM/TIPIN expression data from the publicly accessible TCGA online database, Western blot analysis, and RT-qPCR in a panel of melanoma cell lines. Lentivirus-mediated TIM/TIPIN knockdown in A375 melanoma cells was used to examine proliferation, colony formation, and apoptosis. A xenograft tumor formation assay was also performed. The TIM/TIPIN complex is frequently overexpressed in melanoma cells compared to normal melanocytes. We also discovered that the overexpression of TIM and TIPIN was significantly associated with poorer prognosis of melanoma patients. Furthermore, we observed that shRNA-mediated knockdown of TIM and TIPIN reduced cell viability and proliferation due to the induction of apoptosis and increased levels of γH2AX, a marker of DNA damage. In a xenograft tumor nude mouse model, shRNA-knockdown of TIM/TIPIN significantly reduced tumor growth. Our results suggest that the TIM/TIPIN complex plays an important role in tumorigenesis of melanoma, which might reveal novel approaches for the development of new melanoma therapies. Our studies also provide a beginning structural basis for understanding the assembly of the TIM/TIPIN complex. Further mechanistic investigations are needed to determine the complex's potential as a biomarker of melanoma susceptibility. Targeting TIM/TIPIN might be a potential therapeutic strategy against melanoma.
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http://dx.doi.org/10.18632/oncotarget.27572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244016PMC
May 2020

Drp1-dependent remodeling of mitochondrial morphology triggered by EBV-LMP1 increases cisplatin resistance.

Signal Transduct Target Ther 2020 05 20;5(1):56. Epub 2020 May 20.

Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, 410078, China.

Latent membrane protein 1 (LMP1) is a major Epstein-Barr virus (EBV)-encoded oncoprotein involved in latency infection that regulates mitochondrial functions to facilitate cell survival. Recently, mitochondrial fission has been demonstrated as a crucial mechanism in oncovirus-mediated carcinogenesis. Mitochondrial dynamin-related protein 1 (Drp1)-mediated mitochondrial fission has an impact on the chemoresistance of cancers. However, the mechanism by which oncogenic stress promotes mitochondrial fission, potentially contributing to tumorigenesis, is not entirely understood. The role of Drp1 in the oncogenesis and prognosis of EBV-LMP1-positive nasopharyngeal carcinoma (NPC) was determined in our study. We show that EBV-LMP1 exhibits a new function in remodeling mitochondrial morphology by activating Drp1. A high level of p-Drp1 (Ser616) or a low level of p-Drp1 (Ser637) correlates with poor overall survival and disease-free survival. Furthermore, the protein level of p-Drp1 (Ser616) is related to the clinical stage (TNM stage) of NPC. Targeting Drp1 impairs mitochondrial function and induces cell death in LMP1-positive NPC cells. In addition, EBV-LMP1 regulates Drp1 through two oncogenic signaling axes, AMPK and cyclin B1/Cdk1, which promote cell survival and cisplatin resistance in NPC. Our findings provide novel insight into the role of EBV-LMP1-driven mitochondrial fission in regulating Drp1 phosphorylation at serine 616 and serine 637. Disruption of Drp1 could be a promising therapeutic strategy for LMP1-positive NPC.
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http://dx.doi.org/10.1038/s41392-020-0151-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237430PMC
May 2020

Induction and Prevention of Gastric Cancer with Combined and Capsaicin Administration and DFMO Treatment, Respectively.

Cancers (Basel) 2020 Mar 28;12(4). Epub 2020 Mar 28.

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

Gastric cancer risk evolves over time due to environmental, dietary, and lifestyle changes, including () infection and consumption of hot peppers (i.e., capsaicin). infection promotes gastric mucosal injury in the early phase of capsaicin exposure. This relationship suggests a need to investigate the mechanism of how both infection and capsaicin contribute to gastric inflammation and lead to gastric cancer. C57-Balb/c mice were infected with the (SS1) strain and then fed capsaicin (0.05% or 0.2 g/kg/day) or not. Consequently, tumor size and phenotype were analyzed to determine the molecular mechanism driving the shift from gastritis to stomach cancer. Moreover, we used 2-difluoromethylornithine (DFMO) in mice to prevent gastric tumorigenesis by reducing inflammation and promoting recovery of disease-free stasis. This study provides evidence showing that a combination of infection and capsaicin consumption leads to gastric carcinogenesis mediated through interleukin-6 (IL-6) stimulation with an incidence rate of 50%. The anti-inflammatory role of DFMO highlights the injurious effect of inflammation in gastric cancer development and the need to reduce gastric inflammation for cancer prevention by inhibiting IL-6. Accordingly, preventive measures such as reduced capsaicin consumption, clearance, and DFMO treatment may lessen gastric cancer incidence.
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http://dx.doi.org/10.3390/cancers12040816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226438PMC
March 2020

Wild-type IDH2 contributes to Epstein-Barr virus-dependent metabolic alterations and tumorigenesis.

Mol Metab 2020 06 18;36:100966. Epub 2020 Feb 18.

Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha 410078, China; Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, China; Molecular Imaging Research Center of Central South University, Changsha 410008, Hunan, China; Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, Changsha 410078, China; National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha 410078, China. Electronic address:

Objective: Epstein-Barr virus (EBV) is a well-recognized oncogenic virus that can induce host cell metabolic reprogramming and tumorigenesis by targeting vital metabolic enzymes or regulators. This study aims to explore the role of wild-type isocitrate dehydrogenase 2 (IDH2) in metabolic reprogramming and tumorigenesis induced by EBV-encoded latent membrane protein 1 (LMP1).

Methods: Mechanistic dissection of wild-type IDH2 in EBV-LMP1-induced tumorigenesis was investigated using western blotting, real-time polymerase chain reaction (PCR), immunochemistry, chromatin immunoprecipitation (ChIP), and luciferase assay. The role of wild-type IDH2 was examined by cell viability assays/Sytox Green staining in vitro and xenograft assays in vivo.

Results: IDH2 over-expression is a prognostic indicator of poorer disease-free survival for patients with head and neck squamous cell carcinoma (HNSCC). IDH2 expression is also upregulated in nasopharyngeal carcinoma (NPC, a subtype of HNSCC) tissues, which is positively correlated with EBV-LMP1 expression. EBV-LMP1 contributes to NPC cell viability and xenograft tumor growth mediated through wild-type IDH2. IDH2-dependent changes in intracellular α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG) contribute to EBV-LMP1-induced tumorigenesis in vitro and in vivo. Elevated serum 2-HG level is associated with high EBV DNA and viral capsid antigen-immunoglobulin A (VCA-IgA) levels in patients with NPC. A significantly positive correlation exists between serum 2-HG level and regional lymph node metastases of NPC. EBV-LMP1 enhances the binding of c-Myc with the IDH2 promoter and transcriptionally activates wild-type IDH2 through c-Myc. Targeting IDH2 decreased intracellular 2-HG levels and survival of EBV-LMP1-positive tumor cells in vitro and in vivo.

Conclusions: Our results demonstrate that the EBV-LMP1/c-Myc/IDH2 signaling axis is critical for EBV-dependent metabolic changes and tumorigenesis, which may provide new insights into EBV-related cancer diagnosis and therapy.
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http://dx.doi.org/10.1016/j.molmet.2020.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109632PMC
June 2020

Natural alkaloid and polyphenol compounds targeting lipid metabolism: Treatment implications in metabolic diseases.

Eur J Pharmacol 2020 Mar 11;870:172922. Epub 2020 Jan 11.

Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, PR China; Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, PR China; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, Hunan, 410078, PR China. Electronic address:

Once the balance between lipid anabolism and catabolism is broken, metabolic disorder will occur in the organism and finally lead to metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD), obesity and cancer. No established therapeutic regimens for treating NAFLD and obesity exist yet. Many natural compounds are extracted from botany, fungi and marine organisms. Importantly, natural compounds are major sources of innovative medicine. In this review, we first elucidate the important roles of lipid metabolism in NAFLD, obesity and cancer. Next, we summarize the action mechanisms of natural compounds including alkaloid, polyphenol targeting lipid metabolism. Therefore, manipulating lipid metabolism to reduce fatty acid availability may be the starting point for improving or even curing lipid metabolism-related diseases. Alkaloid and polyphenol are promising candidates for metabolic diseases to ameliorate lipid metabolism abnormalities.
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http://dx.doi.org/10.1016/j.ejphar.2020.172922DOI Listing
March 2020

Targeting the COX1/2-Driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development.

EBioMedicine 2019 Nov 7;49:145-156. Epub 2019 Nov 7.

The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States. Electronic address:

Background: Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes.

Methods: Patient biopsy samples were evaluated for COX1/2, and thromboxane A2 synthase (TBXAS) expression. Circulating prostaglandins biosynthesis was determined using enzyme immunoassay kits. Anchorage-independent cell growth assay, crystal violet staining assay, and xenograft experiments were conducted to assess BE and EAC cell growth. A surgical mouse model of reflux (i.e., esophagoduodenostomy) was established and samples were analyzed using an enzyme immunoassay kit, immunohistochemistry, immunoblotting, or RT-PCR. Esophageal biopsy samples (pre- and post-intervention) were obtained from a randomized clinical trial in which participants were administered esomeprazole (40 mg) twice daily in combination with an acetylsalicylic acid (ASA) placebo or 81 or 325 mg ASA for 28 days. Esophageal biopsy specimens before and after the intervention period were analyzed.

Findings: COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels. ASA suppressed BE and EAC growth by targeting the TXA2 pathway. Additionally, biopsies from 49 patients (with similar baseline characteristics) showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation.

Interpretation: This study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection.

Funding: Hormel Foundation, Exact Sciences, Pentax Medical, Intromedic and National Cancer.
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http://dx.doi.org/10.1016/j.ebiom.2019.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113183PMC
November 2019

Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia.

Nat Commun 2019 11 7;10(1):5051. Epub 2019 Nov 7.

Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, 1098 Xueyuan Ave, 518060, Shenzhen, China.

The oncogenic fusion protein AML1-ETO retains the ability of AML1 to interact with the enhancer core DNA sequences, but blocks AML1-dependent transcription. Previous studies have shown that post-translational modification of AML1-ETO may play a role in its regulation. Here we report that AML1-ETO-positive patients, with high histone lysine methyltransferase Enhancer of zeste homolog 1 (EZH1) expression, show a worse overall survival than those with lower EZH1 expression. EZH1 knockdown impairs survival and proliferation of AML1-ETO-expressing cells in vitro and in vivo. We find that EZH1 WD domain binds to the AML1-ETO NHR1 domain and methylates AML1-ETO at lysine 43 (Lys43). This requires the EZH1 SET domain, which augments AML1-ETO-dependent repression of tumor suppressor genes. Loss of Lys43 methylation by point mutation or domain deletion impairs AML1-ETO-repressive activity. These findings highlight the role of EZH1 in non-histone lysine methylation, indicating that cooperation between AML1-ETO and EZH1 and AML1-ETO site-specific lysine methylation promote AML1-ETO transcriptional repression in leukemia.
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http://dx.doi.org/10.1038/s41467-019-12960-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838331PMC
November 2019

Trichothecin inhibits invasion and metastasis of colon carcinoma associating with SCD-1-mediated metabolite alteration.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 02 31;1865(2):158540. Epub 2019 Oct 31.

Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, Hunan 410078, China; Molecular Imaging Research Center of Central South University, Changsha 410008, Hunan, China. Electronic address:

Lipid metabolic abnormalities have received intensified concerns and increased de novo synthesis of lipids is recognized as a common feature of many human cancers. Nevertheless, the role of lipid metabolism that confers aggressive properties on human cancers still remains to be revealed. Natural compounds represent an abundant pool of agents for the discovery of novel lead compounds. Trichothecin (TCN) is a sesquiterpenoid originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes. Here, we assess the association of stearoyl-CoA desaturase 1 (SCD-1) over-expression with malignant progression of colorectal cancer (CRC). Based on this association, the effect of TCN on migration and invasion of colon carcinoma cells closely related to the inhibition of SCD-1 is evaluated. We further demonstrate that reduced production of unsaturated fatty acids (FAs) by blocking SCD-1 activity is beneficial for the anti-invasion effect of TCN. The aim of this study was to clarify the mechanistic connection between metabolite alterations induced by metabolic rewiring and the aggressive tumor phenotype and further develop novel pharmacological tools for the intervention of tumor invasion associated with SCD-1-mediated metabolite alterations.
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http://dx.doi.org/10.1016/j.bbalip.2019.158540DOI Listing
February 2020

Knockdown of Pyruvate Kinase M Inhibits Cell Growth and Migration by Reducing NF-kB Activity in Triple-Negative Breast Cancer Cells.

Mol Cells 2019 Sep;42(9):628-636

China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China.

Altered genetic features in cancer cells lead to a high rate of aerobic glycolysis and metabolic reprogramming that is essential for increased cancer cell viability and rapid proliferation. Pyruvate kinase muscle (PKM) is a rate-limiting enzyme in the final step of glycolysis. Herein, we report that PKM is a potential therapeutic target in triple-negative breast cancer (TNBC) cells. We found that PKM1 or PKM2 is highly expressed in TNBC tissues or cells. Knockdown of PKM significantly suppressed cell proliferation and migration, and strongly reduced S phase and induced G2 phase cell cycle arrest by reducing phosphorylation of the CDC2 protein in TNBC cells. Additionally, knockdown of PKM significantly suppressed NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity by reducing the phosphorylation of p65 at serine 536, and also decreased the expression of NF-kB target genes. Taken together, PKM is a potential target that may have therapeutic implications for TNBC cells.
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http://dx.doi.org/10.14348/molcells.2019.0038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776161PMC
September 2019

Fluvastatin Inhibits HMG-CoA Reductase and Prevents Non-Small Cell Lung Carcinogenesis.

Cancer Prev Res (Phila) 2019 Dec 25;12(12):837-848. Epub 2019 Sep 25.

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

Lung cancer is the leading cause of cancer-related death worldwide. However, promising agents for lung cancer prevention are still very limited. Identification of preventive targets and novel effective preventive agents is urgently needed for clinical applications. In this study, we found that fluvastatin targeted 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), which a rate-limiting enzyme in the mevalonate pathway, and inhibited non-small cell lung cancer (NSCLC) tumorigenesis. Initially, we demonstrated that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis and Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0211DOI Listing
December 2019

Scutellarin Suppresses Patient-Derived Xenograft Tumor Growth by Directly Targeting AKT in Esophageal Squamous Cell Carcinoma.

Cancer Prev Res (Phila) 2019 12 25;12(12):849-860. Epub 2019 Sep 25.

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

Scutellarin is a flavonoid compound that is found in It has been reported to exhibit anticancer and anti-inflammation activities. However, the anticancer properties of scutellarin and its molecular targets have not been investigated in esophageal squamous cell carcinoma (ESCC). In the current study, we report that scutellarin is a potential AKT inhibitor that suppresses patient-derived xenograft ESCC tumor growth. To identify possible molecular targets of scutellarin, potential candidate proteins were screened by an kinase assay and Western blotting. We found that scutellarin directly binds to the AKT1/2 proteins and inhibits activities of AKT1/2 The AKT protein is activated in ESCC tissues and knockdown of AKT significantly suppresses growth of ESCC cells. Scutellarin significantly inhibits anchorage-dependent and independent cell growth and induces G phase cell-cycle arrest in ESCC cells. The inhibition of cell growth by scutellarin is dependent on the expression of the AKT protein. Notably, scutellarin strongly suppresses patient-derived xenograft ESCC tumor growth in an mouse model. Taken together, our data suggest that scutellarin is a novel AKT inhibitor that may prevent progression of ESCC.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0244DOI Listing
December 2019

The Role of Deubiquitinases in Oncovirus and Host Interactions.

J Oncol 2019 18;2019:2128410. Epub 2019 Jul 18.

Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410078, China.

Infection-related cancer comprises one-sixth of the global cancer burden. Oncoviruses can directly or indirectly contribute to tumorigenesis. Ubiquitination is a dynamic and reversible posttranslational modification that participates in almost all cellular processes. Hijacking of the ubiquitin system by viruses continues to emerge as a central theme around the viral life cycle. Deubiquitinating enzymes (DUBs) maintain ubiquitin homeostasis by removing ubiquitin modifications from target proteins, thereby altering protein function, stability, and signaling pathways, as well as acting as key mediators between the virus and its host. In this review, we focus on the multiple functions of DUBs in RIG-I-like receptors (RLRs) and stimulator of interferon genes (STING)-mediated antiviral signaling pathways, oncoviruses regulation of NF-B activation, oncoviral life cycle, and the potential of DUB inhibitors as therapeutic strategies.
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http://dx.doi.org/10.1155/2019/2128410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668545PMC
July 2019

Treatment implications of natural compounds targeting lipid metabolism in nonalcoholic fatty liver disease, obesity and cancer.

Int J Biol Sci 2019 4;15(8):1654-1663. Epub 2019 Jun 4.

Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.

Metabolic disorders can lead to a scarcity or excess of certain metabolites such as glucose, lipids, proteins, purines, and metal ions, which provide the biochemical foundation and directly contribute to the etiology of metabolic diseases. Nonalcoholic fatty liver disease, obesity, and cancer are common metabolic disorders closely associated with abnormal lipid metabolism. In this review, we first describe the regulatory machinery of lipid metabolism and its deregulation in metabolic diseases. Next, we enumerate and integrate the mechanism of action of some natural compounds, including terpenoids and flavonoids, to ameliorate the development of metabolic diseases by targeting lipid metabolism. Medicinal natural products have an established history of use in health care and therapy. Natural compounds might provide a good source of potential therapeutic agents for treating or preventing metabolic diseases with lipid metabolic abnormalities.
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http://dx.doi.org/10.7150/ijbs.33837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643217PMC
April 2020

CELF2 suppresses non-small cell lung carcinoma growth by inhibiting the PREX2-PTEN interaction.

Carcinogenesis 2020 05;41(3):377-389

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

The phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway is important in the regulation of cell proliferation through its production of phosphatidylinositol 3,4,5-triphosphate (PIP3). Activation of this pathway is frequently observed in human cancers, including non-small cell lung carcinoma. The PI3-K/Akt pathway is negatively regulated by the dual-specificity phosphatase and tensin homolog (PTEN) protein. PTEN acts as a direct antagonist of PI3-K by dephosphorylating PIP3. Studies have shown that PTEN phosphatase activity is inhibited by PREX2, a guanine nucleotide exchanger factor (GEF). Multiple studies revealed that CELF2, an RNA binding protein, cooperates synergistically with PTEN as a tumor suppressor in multiple cancers. However, the underlying mechanism as to how CELF2 enhances PTEN activity remains unclear. Here, we report that CELF2 interacts with PREX2 and reduces the association of PREX2 with PTEN. Consistent with this observation, PTEN phosphatase activity is upregulated with CELF2 overexpression. In addition, overexpression of CELF2 represses both Akt phosphorylation and cell proliferation only in the presence of PTEN. In an ex vivo study, CELF2 gene delivery could significantly inhibit patient-derived xenografts (PDX) tumor growth. To further investigate the clinical relevance of this finding, we analyzed 87 paired clinical lung adenocarcinoma samples and the results showed that CELF2 protein expression is downregulated in tumor tissues and associated with poor prognosis. The CELF2 gene is located on the chromosome 10p arm, a region frequently lost in human cancers, including breast invasive carcinoma, low-grade glioma and glioblastoma. Analysis of TCGA datasets showed that CELF2 expression is also associated with shorter patient survival time in all these cancers. Overall, our work suggests that CELF2 plays a novel role in PI3-K signaling by antagonizing the oncogenic effect of PREX2.
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http://dx.doi.org/10.1093/carcin/bgz113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221505PMC
May 2020
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