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Siregar KAAK, Syaifie PH, Jauhar MM, Arda AG, Rochman NT, Kustiawan PM, Mardliyati E. Revealing curcumin therapeutic targets on SRC, PPARG, MAPK8 and HSP90 as liver cirrhosis therapy based on comprehensive bioinformatic study. J Biomol Struct Dyn 2025; 43:3172-3189. [PMID: 38217310 DOI: 10.1080/07391102.2023.2301534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 12/09/2023] [Indexed: 01/15/2024]
Abstract
Cirrhosis naturally progresses through three stages: compensated, decompensated, and late decompensated, which carry an elevated risk of death. Although curcumin's anti-cirrhosis effects have been studied, underlying mechanism in preventing cirrhosis progression and the correlation between curcumin's action with upregulated genes remains insufficiently explored. In this study, we employed network pharmacology approach to construct a drug-target-disease network through bioinformatics and validate the findings with molecular docking and dynamic simulation. The curcumin-targeted liver cirrhosis network encompassed 54 nodes with 282 edges in protein-protein interactions (PPI) network. By utilizing network centrality analysis, we identified eight crucial genes. KEGG enrichment pathway revealed that these crucial genes are involved in pathway of cancer, endocrine resistance, estrogen signaling, chemical carcinogenesis-receptor activation, lipid metabolism, and atherosclerosis. Notably, these eight genes predominantly participate in cancer-related pathways. Further investigation revealed upregulation of four genes and downregulation of four others in hepatocellular carcinoma patients. These upregulated genes-MAPK8, SRC, PPARG, and HSP90AA1-strongly correlated with reduced survival probability in liver hepatocellular carcinoma patients with survival times approximately under 4000 days (∼11 years). Molecular docking and molecular dynamic results exhibited curcumin's superior binding affinities and stability compared to native ligands of MAPK8, SRC, PPARG, and HSP90AA1 within 50 ns simulations. Moreover, MM-GBSA analysis showed stronger binding energy of curcumin to MAPK8, SRC, and HSP90AA1 than native ligand. In conclusion, this study provides valuable insights into curcumin's potential mechanisms in preventing liver cirrhosis progression, specifically in HCC. These findings offer a theoretical basis for further pharmacological research into anti-HCC effect of curcumin.
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Affiliation(s)
- Khalish Arsy Al Khairy Siregar
- Faculty of Pharmacy, Universitas Muhammadiyah Kalimantan Timur, Samarinda, Indonesia
- Center of Excellence Life Sciences, Nano Center Indonesia, South Tangerang, Indonesia
| | - Putri Hawa Syaifie
- Center of Excellence Life Sciences, Nano Center Indonesia, South Tangerang, Indonesia
| | | | - Adzani Gaisani Arda
- Center of Excellence Life Sciences, Nano Center Indonesia, South Tangerang, Indonesia
| | - Nurul Taufiqu Rochman
- Center of Excellence Life Sciences, Nano Center Indonesia, South Tangerang, Indonesia
- Research Center for Advanced Material, National Research and Innovation Agency (BRIN), South Tangerang, Indonesia
| | | | - Etik Mardliyati
- Center of Excellence Life Sciences, Nano Center Indonesia, South Tangerang, Indonesia
- Research Center for Vaccine and Drug, National Research and Innovation Agency (BRIN), Bogor, Indonesia
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2
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Alkafaas SS, Khedr SA, ElKafas SS, Hafez W, Loutfy SA, Sakran M, Janković N. Targeting JNK kinase inhibitors via molecular docking: A promising strategy to address tumorigenesis and drug resistance. Bioorg Chem 2024; 153:107776. [PMID: 39276490 DOI: 10.1016/j.bioorg.2024.107776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/13/2024] [Accepted: 08/28/2024] [Indexed: 09/17/2024]
Abstract
Among members of the mitogen-activated protein kinase (MAPK) family, c-Jun N-terminal kinases (JNKs) are vital for cellular responses to stress, inflammation, and apoptosis. Recent advances have highlighted their important implications in cancer biology, where dysregulated JNK signalling plays a role in the growth, progression, and metastasis of tumors. The present understanding of JNK kinase and its function in the etiology of cancer is summarized in this review. By modifying a number of downstream targets, such as transcription factors, apoptotic regulators, and cell cycle proteins, JNKs exert diverse effects on cancer cells. Apoptosis avoidance, cell survival, and proliferation are all promoted by abnormal JNK activation in many types of cancer, which leads to tumor growth and resistance to treatment. JNKs also affect the tumour microenvironment by controlling the generation of inflammatory cytokines, angiogenesis, and immune cell activity. However, challenges remain in deciphering the context-specific roles of JNK isoforms and their intricate crosstalk with other signalling pathways within the complex tumor environment. Further research is warranted to delineate the precise mechanisms underlying JNK-mediated tumorigenesis and to develop tailored therapeutic strategies targeting JNK signalling to improve cancer management. The review emphasizes the role of JNK kinases in cancer biology, as well as their potential as pharmaceutical targets for precision oncology therapy and cancer resistance. Also, this review summarizes all the available promising JNK inhibitors that are suggested to promote the responsiveness of cancer cells to cancer treatment.
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Affiliation(s)
- Samar Sami Alkafaas
- Molecular Cell Biology Unit, Division of Biochemistry, Department of Chemistry, Faculty of Science, Tanta University, 31527, Egypt.
| | - Sohila A Khedr
- Industrial Biotechnology Department, Faculty of Science, Tanta University, Tanta 31733, Egypt
| | - Sara Samy ElKafas
- Production Engineering and Mechanical Design Department, Faculty of Engineering, Menofia University, Menofia, Egypt; Faculty of Control System and Robotics, ITMO University, Saint-Petersburg, Russia
| | - Wael Hafez
- NMC Royal Hospital, 16th St - Khalifa City - SE-4 - Abu Dhabi, United Arab Emirates; Department of Internal Medicine, Medical Research and Clinical Studies Institute, The National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, Cairo Governorate 12622, Egypt
| | - Samah A Loutfy
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohamed Sakran
- Biochemistry Department, Faculty of Science, University of Tabuk, Tabuk 47512, Saudi Arabia
| | - Nenad Janković
- Institute for Information Technologies Kragujevac, Department of Science, University of Kragujevac, Jovana Cvijića bb, 34000 Kragujevac, Serbia.
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Ikumawoyi VO, Lynch KD, Iverson DT, Call MR, Yue GE, Prasad B, Clarke JD. Microcystin-LR activates serine/threonine kinases and alters the phosphoproteome in human HepaRG cells. Toxicon 2024; 249:108072. [PMID: 39154757 PMCID: PMC11402562 DOI: 10.1016/j.toxicon.2024.108072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/09/2024] [Accepted: 08/14/2024] [Indexed: 08/20/2024]
Abstract
Microcystin-LR (MCLR) exposure has been associated with development of hepatocellular carcinoma (HCC). Many of the carcinogenic mechanisms for MCLR have been attributed to the induction of cell survival and proliferation through altered protein phosphorylation pathways by inhibition of protein phosphatases 1 (PP1) and PP2A. The current study determined MCLR effects on the phosphoproteome in human HepaRG cells. Differentiated HepaRG cells were treated with either vehicle or MCLR followed by phosphoproteomic analysis and Western blotting of MAPK-activated proteins. MCLR decreased cell viability at 24 h at doses as low as 0.03 μM. MCLR also caused a dose-dependent increase in phosphorylation of signaling and stress kinases. The number of decreased phosphosites by 0.1 μM MCLR was similar between the 2 h (212) and 24 h (154) timepoints. In contrast, a greater number of phosphosites were increased at 24 h (567) versus the 2 h timepoint (136), indicating the hyperphosphorylation state caused by MCLR-mediated inhibition of PPs is time-dependent. A kinase perturbation analysis predicted that MCLR exposure at both 2 h and 24 h increased the function of aurora kinase B (AURKB), checkpoint kinase 1 (CHEK1), and serum and glucocorticoid-regulated kinase 1 (SGK1). STRING database analysis of the phosphosites altered by MCLR exposure revealed pathways associated with cell proliferation and survival, including ribosomal protein S6 kinase (RSK), and vascular endothelial growth factor receptor (VEGFR2)-mediated vascular permeability. In addition, several cancer-related KEGG pathways were enriched at both 2 h and 24 h timepoints, and multiple cancer-related disease-gene associations were identified at the 24 h timepoint. Many of the kinases and pathways described above play crucial roles in the development of HCC by affecting processes such as invasion and metastasis. Overall, our data indicate that MCLR-mediated changes in protein phosphorylation involve biological pathways related to carcinogenesis that may contribute to the development of HCC.
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Affiliation(s)
- Victor O Ikumawoyi
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States
| | - Katherine D Lynch
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States
| | - Dayne T Iverson
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States
| | - M Ridge Call
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States
| | - Guihua Eileen Yue
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States
| | - Bhagwat Prasad
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States
| | - John D Clarke
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States.
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Zhou P, Yao W, Liu L, Yan Q, Chen X, Wei X, Ding S, Lv Z, Zhu F. SPG21, a potential oncogene targeted by miR-128-3p, amplifies HBx-induced carcinogenesis and chemoresistance via activation of TRPM7-mediated JNK pathway in hepatocellular carcinoma. Cell Oncol (Dordr) 2024; 47:1757-1778. [PMID: 38753154 DOI: 10.1007/s13402-024-00955-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2024] [Indexed: 07/31/2024] Open
Abstract
PURPOSE Chronic hepatitis B virus (HBV) infection is the primary risk factor for the malignant progression of hepatocellular carcinoma (HCC). It has been reported that HBV X protein (HBx) possesses oncogenic properties, promoting hepatocarcinogenesis and chemoresistance. However, the detailed molecular mechanisms are not fully understood. Here, we aim to investigate the effects of miR-128-3p/SPG21 axis on HBx-induced hepatocarcinogenesis and chemoresistance. METHODS The expression of SPG21 in HCC was determined using bioinformatics analysis, quantitative real-time PCR (qRT-PCR), western blotting, and immunohistochemistry (IHC). The roles of SPG21 in HCC were elucidated through a series of in vitro and in vivo experiments, including real-time cellular analysis (RTCA), matrigel invasion assay, and xenograft mouse model. Pharmacologic treatment and flow cytometry were performed to demonstrate the potential mechanism of SPG21 in HCC. RESULTS SPG21 expression was elevated in HCC tissues compared to adjacent non-tumor tissues (NTs). Moreover, higher SPG21 expression correlated with poor overall survival. Functional assays revealed that SPG21 fostered HCC tumorigenesis and invasion. MiR-128-3p, which targeted SPG21, was downregulated in HCC tissues. Subsequent analyses showed that HBx amplified TRPM7-mediated calcium influx via miR-128-3p/SPG21, thereby activating the c-Jun N-terminal kinase (JNK) pathway. Furthermore, HBx inhibited doxorubicin-induced apoptosis by engaging the JNK pathway through miR-128-3p/SPG21. CONCLUSION The study suggested that SPG21, targeted by miR-128-3p, might be involved in enhancing HBx-induced carcinogenesis and doxorubicin resistance in HCC via the TRPM7/Ca2+/JNK signaling pathway. This insight suggested that SPG21 could be recognized as a potential oncogene, offering a novel perspective on its role as a prognostic factor and a therapeutic target in the context of HCC.
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Affiliation(s)
- Ping Zhou
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, 430071, Wuhan, China
| | - Wei Yao
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, 430071, Wuhan, China
| | - Lijuan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, 430071, Wuhan, China
| | - Qiujin Yan
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, 430071, Wuhan, China
| | - Xiaobei Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, 430060, Wuhan, China
| | - Xiaocui Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, 430071, Wuhan, China
| | - Shuang Ding
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, 430071, Wuhan, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, 430071, Wuhan, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, 430071, Wuhan, China.
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, 430071, Wuhan, China.
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5
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Li D, Gao Y, Wang C, Hu L. Proteomic and phosphoproteomic profiling of urinary small extracellular vesicles in hepatocellular carcinoma. Analyst 2024; 149:4378-4387. [PMID: 38995156 DOI: 10.1039/d4an00660g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/13/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and a major cause of cancer-related mortality worldwide. Small extracellular vesicles (sEVs) are heterogeneous populations of membrane-structured vesicles that can be found in many biological fluids and are currently considered as a potential source of disease-associated biomarkers for diagnosis. The purpose of this study was to define the proteomic and phosphoproteomic landscape of urinary sEVs in patients with HCC. Mass spectrometry-based methods were used to detect the global proteome and phosphoproteome profiles of sEVs isolated by differential ultracentrifugation. Label-free quantitation analysis showed that 348 differentially expressed proteins (DEPs) and 548 differentially expressed phosphoproteins (DEPPs) were identified in the HCC group. Among them, multiple phosphoproteins related to HCC, including HSP90AA1, IQGAP1, MTOR, and PRKCA, were shown to be upregulated in the HCC group. Pathway enrichment analysis indicated that the upregulated DEPPs participate in the regulation of autophagy, proteoglycans in cancer, and the MAPK/mTOR/Rap1 signaling pathway. Furthermore, kinase-substrate enrichment analysis revealed activation of MTOR, AKT1, MAP2Ks, and MAPKs family kinases in HCC-derived sEVs, indicating that dysregulation of the MAPK and mTOR signaling pathways may be the primary sEV-mediated molecular mechanisms involved in the development and progression of HCC. This study demonstrated that urinary sEVs are enriched in proteomic and phosphoproteomic signatures that could be further explored for their potential use in early HCC diagnostic and therapeutic applications.
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Affiliation(s)
- Dejun Li
- Center for Supramolecular Chemical Biology, School of Life Sciences, Jilin University, Changchun 130012, China.
- Prenatal Diagnosis Center, Reproductive Medicine Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Yujun Gao
- Center for Supramolecular Chemical Biology, School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Chong Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, China.
| | - Lianghai Hu
- Center for Supramolecular Chemical Biology, School of Life Sciences, Jilin University, Changchun 130012, China.
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Yan W, Rao D, Fan F, Liang H, Zhang Z, Dong H. Hepatitis B virus X protein and TGF-β: partners in the carcinogenic journey of hepatocellular carcinoma. Front Oncol 2024; 14:1407434. [PMID: 38962270 PMCID: PMC11220127 DOI: 10.3389/fonc.2024.1407434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/21/2024] [Indexed: 07/05/2024] Open
Abstract
Hepatitis B infection is substantially associated with the development of liver cancer globally, with the prevalence of hepatocellular carcinoma (HCC) cases exceeding 50%. Hepatitis B virus (HBV) encodes the Hepatitis B virus X (HBx) protein, a pleiotropic regulatory protein necessary for the transcription of the HBV covalently closed circular DNA (cccDNA) microchromosome. In previous studies, HBV-associated HCC was revealed to be affected by HBx in multiple signaling pathways, resulting in genetic mutations and epigenetic modifications in proto-oncogenes and tumor suppressor genes. In addition, transforming growth factor-β (TGF-β) has dichotomous potentials at various phases of malignancy as it is a crucial signaling pathway that regulates multiple cellular and physiological processes. In early HCC, TGF-β has a significant antitumor effect, whereas in advanced HCC, it promotes malignant progression. TGF-β interacts with the HBx protein in HCC, regulating the pathogenesis of HCC. This review summarizes the respective and combined functions of HBx and TGB-β in HCC occurrence and development.
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Affiliation(s)
- Wei Yan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Dean Rao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Feimu Fan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Zunyi Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Hanhua Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
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Bakiri L, Hasenfuss SC, Guío-Carrión A, Thomsen MK, Hasselblatt P, Wagner EF. Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc. Proc Natl Acad Sci U S A 2024; 121:e2404188121. [PMID: 38657045 PMCID: PMC11067056 DOI: 10.1073/pnas.2404188121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the Activator Protein-1 (AP-1) (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens (Fra-) 1 and 2 is unknown. Here, we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis, and Pparγ-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently under direct regulation by AP-1 through a conserved distal 3' enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the Bromodomain and Extra-Terminal motif inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.
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Affiliation(s)
- Latifa Bakiri
- Laboratory Genes and Disease, Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
- Genes, Development and Disease Group, National Cancer Research Centre, 28029, Madrid, Spain
| | - Sebastian C. Hasenfuss
- Genes, Development and Disease Group, National Cancer Research Centre, 28029, Madrid, Spain
| | - Ana Guío-Carrión
- Genes, Development and Disease Group, National Cancer Research Centre, 28029, Madrid, Spain
| | - Martin K. Thomsen
- Department of Biomedicine, University of Aarhus, 8000, Aarhus, Denmark
| | - Peter Hasselblatt
- Department of Medicine II, University Hospital and Faculty of Medicine, 79106, Freiburg, Germany
| | - Erwin F. Wagner
- Laboratory Genes and Disease, Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
- Laboratory Genes and Disease, Department of Dermatology, Medical University of Vienna, 1090, Vienna, Austria
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Chen H, Zhou H, Wu B, Lu H, Zhang J, Zhang Y, Gu Y, Zhou G, Xiang J, Yang J. Physical activity and exercise in liver cancer. LIVER RESEARCH 2024; 8:22-33. [PMID: 39959031 PMCID: PMC11771262 DOI: 10.1016/j.livres.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/04/2024] [Accepted: 03/04/2024] [Indexed: 02/18/2025]
Abstract
Sarcopenia and physical deconditioning are common complications in patients with liver cancer, which are frequently caused by insufficient physical activity and poor nutritional status, resulting in physical frailty and a significant impact on the patient's physical fitness. Notably, sarcopenia, frailty, and poor cardiopulmonary endurance have all been linked to higher mortality rates among patients with liver cancer. Exercise intervention significantly improves various health parameters in liver cancer patients, including metabolic syndrome, muscle wasting, cardiorespiratory endurance, health-related quality of life, and reduction in hepatic venous pressure gradient. However, the link between physical exercise and liver cancer is commonly overlooked. In this article, we will examine the impact of exercise on liver cancer and present the most recent evidence on the best types of exercise for various stages of liver cancer. This article also summarizes and discusses the molecular mechanisms that control metabolism and systemic immune function in tumors. In brief, physical exercise should be considered an important intervention in the prevention and treatment of liver cancer and its complications.
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Affiliation(s)
- Haiyan Chen
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
- School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Huimin Zhou
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
- School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Bo Wu
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
- School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Hanxiao Lu
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
- School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Jie Zhang
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
| | - Yan Zhang
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
| | - Yuanlong Gu
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
| | - Guangwen Zhou
- Department of General Surgery, Shanghai Sixth People's Hospital, Shanghai, China
| | - Jie Xiang
- Department of Endocrinology, Wuxi Mingci Cardiovascular Hospital, Wuxi, Jiangsu, China
| | - Jun Yang
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
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9
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Manoharan S, Saha S, Murugesan K, Santhakumar A, Perumal E. Natural bioactive compounds and STAT3 against hepatocellular carcinoma: An update. Life Sci 2024; 337:122351. [PMID: 38103726 DOI: 10.1016/j.lfs.2023.122351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/23/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Hepatocellular carcinoma (HCC) is a challenging and very fatal liver cancer. The signal transducer and activator of transcription 3 (STAT3) pathway is a crucial regulator of tumor development and are ubiquitously active in HCC. Therefore, targeting STAT3 has emerged as a promising approach for preventing and treating HCC. Various natural bioactive compounds (NBCs) have been proven to target STAT3 and have the potential to prevent and treat HCC as STAT3 inhibitors. Numerous kinds of STAT3 inhibitors have been identified, including small molecule inhibitors, peptide inhibitors, and oligonucleotide inhibitors. Due to the undesirable side effects of the conventional therapeutic drugs against HCC, the focus is shifted to NBCs derived from plants and other natural sources. NBCs can be broadly classified into the categories of terpenes, alkaloids, carotenoids, and phenols. Most of the compounds belong to the family of terpenes, which prevent tumorigenesis by inhibiting STAT3 nuclear translocation. Further, through STAT3 inhibition, terpenes downregulate matrix metalloprotease 2 (MMP2), matrix metalloprotease 9 (MMP9) and vascular endothelial growth factor (VEGF), modulating metastasis. Terpenes also suppress the anti-apoptotic proteins and cell cycle markers. This review provides comprehensive information related to STAT3 abrogation by NBCs in HCC with in vitro and in vivo evidences.
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Affiliation(s)
- Suryaa Manoharan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Shreejit Saha
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Krishnasanthiya Murugesan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Aksayakeerthana Santhakumar
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Ekambaram Perumal
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India.
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10
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Yu J, Li X, Cao J, Zhu T, Liang S, Du L, Cao M, Wang H, Zhang Y, Zhou Y, Shen B, Feng J, Zhang J, Wang J, Jin J. Components of the JNK-MAPK pathway play distinct roles in hepatocellular carcinoma. J Cancer Res Clin Oncol 2023; 149:17495-17509. [PMID: 37902853 DOI: 10.1007/s00432-023-05473-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/10/2023] [Indexed: 11/01/2023]
Abstract
PURPOSE Mitogen-activated protein kinases (MAPK), specifically the c-Jun N-terminal kinase (JNK)-MAPK subfamily, play a crucial role in the development of various cancers, including hepatocellular carcinoma (HCC). However, the specific roles of JNK1/2 and their upstream regulators, MKK4/7, in HCC carcinogenesis remain unclear. METHODS In this study, we performed differential expression analysis of JNK-MAPK components at both the transcriptome and protein levels using TCGA and HPA databases. We utilized Kaplan-Meier survival plots and receiver operating characteristic (ROC) curve analysis to evaluate the prognostic performance of a risk scoring model based on these components in the TCGA-HCC cohort. Additionally, we conducted immunoblotting, apoptosis analysis with FACS and soft agar assays to investigate the response of JNK-MAPK pathway components to various death stimuli (TRAIL, TNF-α, anisomycin, and etoposide) in HCC cell lines. RESULTS JNK1/2 and MKK7 levels were significantly upregulated in HCC samples compared to paracarcinoma tissues, whereas MKK4 was downregulated. ROC analyses suggested that JNK2 and MKK7 may serve as suitable diagnostic genes for HCC, and high JNK2 expression correlated with significantly poorer overall survival. Knockdown of JNK1 enhanced TRAIL-induced apoptosis in hepatoma cells, while JNK2 knockdown reduced TNF-α/cycloheximide (CHX)-and anisomycin-induced apoptosis. Neither JNK1 nor JNK2 knockdown affected etoposide-induced apoptosis. Furthermore, MKK7 knockdown augmented TNF-α/CHX- and TRAIL-induced apoptosis and inhibited colony formation in hepatoma cells. CONCLUSION Targeting MKK7, rather than JNK1/2 or MKK4, may be a promising therapeutic strategy to inhibit the JNK-MAPK pathway in HCC therapy.
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Affiliation(s)
- Jijun Yu
- School of Basic Medicine, Hainan Medical University, Haikou, 571199, China
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China
| | - Xinying Li
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China
| | - Junxia Cao
- Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Ting Zhu
- Beijing No. 80 High School, Beijing, 100102, China
| | - Shuifeng Liang
- School of Basic Medicine, Hainan Medical University, Haikou, 571199, China
| | - Le Du
- School of Basic Medicine, Hainan Medical University, Haikou, 571199, China
| | - Meng Cao
- School of Basic Medicine, Hainan Medical University, Haikou, 571199, China
| | - Haitao Wang
- Department of Hematology, The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100071, China
| | - Yaolin Zhang
- Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Yinxi Zhou
- School of Basic Medicine, Hainan Medical University, Haikou, 571199, China
| | - Beifen Shen
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China
- Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Jiannan Feng
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China
| | - Jiyan Zhang
- Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
| | - Jing Wang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
| | - Jianfeng Jin
- School of Basic Medicine, Hainan Medical University, Haikou, 571199, China.
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11
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Talamantes S, Lisjak M, Gilglioni EH, Llamoza-Torres CJ, Ramos-Molina B, Gurzov EN. Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma. JHEP Rep 2023; 5:100811. [PMID: 37575883 PMCID: PMC10413159 DOI: 10.1016/j.jhepr.2023.100811] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 05/01/2023] [Accepted: 05/08/2023] [Indexed: 08/15/2023] Open
Abstract
Obesity-related complications such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are well-established risk factors for the development of hepatocellular carcinoma (HCC). This review provides insights into the molecular mechanisms that underlie the role of steatosis, hyperinsulinemia and hepatic inflammation in HCC development and progression. We focus on recent findings linking intracellular pathways and transcription factors that can trigger the reprogramming of hepatic cells. In addition, we highlight the role of enzymes in dysregulated metabolic activity and consequent dysfunctional signalling. Finally, we discuss the potential uses and challenges of novel therapeutic strategies to prevent and treat NAFLD/T2D-associated HCC.
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Affiliation(s)
- Stephanie Talamantes
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Michela Lisjak
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Eduardo H. Gilglioni
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Camilo J. Llamoza-Torres
- Department of Hepatology, Virgen de la Arrixaca University Hospital, Murcia, 30120, Spain
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
| | - Bruno Ramos-Molina
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
| | - Esteban N. Gurzov
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
- WELBIO Department, WEL Research Institute, Avenue Pasteur 6, Wavre, 1300, Belgium
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12
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Veltman CHJ, Pennings JLA, van de Water B, Luijten M. An Adverse Outcome Pathway Network for Chemically Induced Oxidative Stress Leading to (Non)genotoxic Carcinogenesis. Chem Res Toxicol 2023. [PMID: 37156502 DOI: 10.1021/acs.chemrestox.2c00396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Nongenotoxic (NGTX) carcinogens induce cancer via other mechanisms than direct DNA damage. A recognized mode of action for NGTX carcinogens is induction of oxidative stress, a state in which the amount of oxidants in a cell exceeds its antioxidant capacity, leading to regenerative proliferation. Currently, carcinogenicity assessment of environmental chemicals primarily relies on genetic toxicity end points. Since NGTX carcinogens lack genotoxic potential, these chemicals may remain undetected in such evaluations. To enhance the predictivity of test strategies for carcinogenicity assessment, a shift toward mechanism-based approaches is required. Here, we present an adverse outcome pathway (AOP) network for chemically induced oxidative stress leading to (NGTX) carcinogenesis. To develop this AOP network, we first investigated the role of oxidative stress in the various cancer hallmarks. Next, possible mechanisms for chemical induction of oxidative stress and the biological effects of oxidative damage to macromolecules were considered. This resulted in an AOP network, of which associated uncertainties were explored. Ultimately, development of AOP networks relevant for carcinogenesis in humans will aid the transition to a mechanism-based, human relevant carcinogenicity assessment that involves a substantially lower number of laboratory animals.
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Affiliation(s)
- Christina H J Veltman
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands
| | - Jeroen L A Pennings
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
| | - Bob van de Water
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands
| | - Mirjam Luijten
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
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13
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Chen XR, Igumenova TI. Regulation of eukaryotic protein kinases by Pin1, a peptidyl-prolyl isomerase. Adv Biol Regul 2023; 87:100938. [PMID: 36496344 PMCID: PMC9992314 DOI: 10.1016/j.jbior.2022.100938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022]
Abstract
The peptidyl-prolyl isomerase Pin1 cooperates with proline-directed kinases and phosphatases to regulate multiple oncogenic pathways. Pin1 specifically recognizes phosphorylated Ser/Thr-Pro motifs in proteins and catalyzes their cis-trans isomerization. The Pin1-catalyzed conformational changes determine the stability, activity, and subcellular localization of numerous protein substrates. We conducted a survey of eukaryotic protein kinases that are regulated by Pin1 and whose Pin1 binding sites have been identified. Our analyses reveal that Pin1 target sites in kinases do not fall exclusively within the intrinsically disordered regions of these enzymes. Rather, they fall into three groups based on their location: (i) within the catalytic kinase domain, (ii) in the C-terminal kinase region, and (iii) in regulatory domains. Some of the kinases downregulated by Pin1 activity are tumor-suppressing, and all kinases upregulated by Pin1 activity are functionally pro-oncogenic. These findings further reinforce the rationale for developing Pin1-specific inhibitors as attractive pharmaceuticals for cancer therapy.
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Affiliation(s)
- Xiao-Ru Chen
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, 77843, USA
| | - Tatyana I Igumenova
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, 77843, USA.
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14
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Wang L, Guo M, Gao L, Liu K, Bai J, Liu Z. JNK2 Promotes Progression of Esophageal Squamous Cell Carcinoma via Inhibiting Axin2. Curr Pharm Des 2023; 29:2977-2987. [PMID: 37957865 DOI: 10.2174/0113816128261624231030110157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 09/17/2023] [Accepted: 09/25/2023] [Indexed: 11/15/2023]
Abstract
INTRODUCTION The dysregulation of the c-Jun NH2-terminal kinase (JNK) pathway has been increasingly reported in human malignancies. Aberrant expression of the JNK pathway has also been implicated in the progression of Esophageal Squamous Cell Carcinoma (ESCC). However, the specific role and regulatory mechanisms of JNK2 in ESCC have not been extensively investigated. METHODS In this study, we examined JNK2 expression in patient samples and performed experiments involving the knockdown and inhibition of the JNK2 in ESCC cell lines. RESULTS Higher JNK2 expression was observed in tumor tissues compared to adjacent tissues. JNK2 overexpression was associated with advanced disease stages and poor prognosis. Furthermore, knockdown or inhibition of JNK2 in ESCC cell lines resulted in a decrease in cell proliferation and migration. CONCLUSION Additionally, a significant decrease in the expression of β-catenin and vimentin, along with an increase in the expression of Axin2, was observed upon downregulation of JNK2. Our study provides insight into the role of JNK2 in ESCC and its potential regulatory mechanism, offering a potential therapeutic strategy for ESCC patients with aberrant JNK2 expression.
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Affiliation(s)
- Lulu Wang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Fourth Medical Center of PLA General Hospital, Xijing Hospital of Digestive Diseases, Air Force Medical University, Xi'an, China
| | - Meng Guo
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Fourth Medical Center of PLA General Hospital, Xijing Hospital of Digestive Diseases, Air Force Medical University, Xi'an, China
| | - Li Gao
- Fourth Medical Center of PLA General Hospital, Xijing Hospital of Digestive Diseases, Air Force Medical University (Fourth Military Medical University), Xi'an, China
| | - Kai Liu
- Fourth Medical Center of PLA General Hospital, Xijing Hospital of Digestive Diseases, Air Force Medical University (Fourth Military Medical University), Xi'an, China
| | - Jiawei Bai
- Fourth Medical Center of PLA General Hospital, Xijing Hospital of Digestive Diseases, Air Force Medical University (Fourth Military Medical University), Xi'an, China
- School of Medicine, Yan'an University, Yan'an, China
| | - Zhiguo Liu
- Fourth Medical Center of PLA General Hospital, Xijing Hospital of Digestive Diseases, Air Force Medical University (Fourth Military Medical University), Xi'an, China
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15
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Disorders of cancer metabolism: The therapeutic potential of cannabinoids. Biomed Pharmacother 2023; 157:113993. [PMID: 36379120 DOI: 10.1016/j.biopha.2022.113993] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/07/2022] [Accepted: 11/07/2022] [Indexed: 11/13/2022] Open
Abstract
Abnormal energy metabolism, as one of the important hallmarks of cancer, was induced by multiple carcinogenic factors and tumor-specific microenvironments. It comprises aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis. Considering that metabolic reprogramming provides various nutrients for tumor survival and development, it has been considered a potential target for cancer therapy. Cannabinoids have been shown to exhibit a variety of anticancer activities by unclear mechanisms. This paper first reviews the recent progress of related signaling pathways (reactive oxygen species (ROS), AMP-activated protein kinase (AMPK), mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), hypoxia-inducible factor-1alpha (HIF-1α), and p53) mediating the reprogramming of cancer metabolism (including glucose metabolism, lipid metabolism, and amino acid metabolism). Then we comprehensively explore the latest discoveries and possible mechanisms of the anticancer effects of cannabinoids through the regulation of the above-mentioned related signaling pathways, to provide new targets and insights for cancer prevention and treatment.
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16
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Non-kinase targeting of oncogenic c-Jun N-terminal kinase (JNK) signaling: the future of clinically viable cancer treatments. Biochem Soc Trans 2022; 50:1823-1836. [PMID: 36454622 PMCID: PMC9788565 DOI: 10.1042/bst20220808] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/28/2022] [Accepted: 11/15/2022] [Indexed: 01/09/2023]
Abstract
c-Jun N-terminal Kinases (JNKs) have been identified as key disease drivers in a number of pathophysiological settings and central oncogenic signaling nodes in various cancers. Their roles in driving primary tumor growth, positively regulating cancer stem cell populations, promoting invasion and facilitating metastatic outgrowth have led JNKs to be considered attractive targets for anti-cancer therapies. However, the homeostatic, apoptotic and tumor-suppressive activities of JNK proteins limit the use of direct JNK inhibitors in a clinical setting. In this review, we will provide an overview of the different JNK targeting strategies developed to date, which include various ATP-competitive, non-kinase and substrate-competitive inhibitors. We aim to summarize their distinct mechanisms of action, review some of the insights they have provided regarding JNK-targeting in cancer, and outline the limitations as well as challenges of all strategies that target JNKs directly. Furthermore, we will highlight alternate drug targets within JNK signaling complexes, including recently identified scaffold proteins, and discuss how these findings may open up novel therapeutic options for targeting discrete oncogenic JNK signaling complexes in specific cancer settings.
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17
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Chen G, Liu ZP. Inferring causal gene regulatory network via GreyNet: From dynamic grey association to causation. Front Bioeng Biotechnol 2022; 10:954610. [PMID: 36237217 PMCID: PMC9551017 DOI: 10.3389/fbioe.2022.954610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/15/2022] [Indexed: 11/23/2022] Open
Abstract
Gene regulatory network (GRN) provides abundant information on gene interactions, which contributes to demonstrating pathology, predicting clinical outcomes, and identifying drug targets. Existing high-throughput experiments provide rich time-series gene expression data to reconstruct the GRN to further gain insights into the mechanism of organisms responding to external stimuli. Numerous machine-learning methods have been proposed to infer gene regulatory networks. Nevertheless, machine learning, especially deep learning, is generally a “black box,” which lacks interpretability. The causality has not been well recognized in GRN inference procedures. In this article, we introduce grey theory integrated with the adaptive sliding window technique to flexibly capture instant gene–gene interactions in the uncertain regulatory system. Then, we incorporate generalized multivariate Granger causality regression methods to transform the dynamic grey association into causation to generate directional regulatory links. We evaluate our model on the DREAM4 in silico benchmark dataset and real-world hepatocellular carcinoma (HCC) time-series data. We achieved competitive results on the DREAM4 compared with other state-of-the-art algorithms and gained meaningful GRN structure on HCC data respectively.
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Affiliation(s)
- Guangyi Chen
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong, China
| | - Zhi-Ping Liu
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong, China
- Center for Intelligent Medicine, Shandong University, Jinan, Shandong, China
- *Correspondence: Zhi-Ping Liu,
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18
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Hung PH, Hsu YC, Chen TH, Ho C, Lin CL. The Histone Demethylase Inhibitor GSK-J4 Is a Therapeutic Target for the Kidney Fibrosis of Diabetic Kidney Disease via DKK1 Modulation. Int J Mol Sci 2022; 23:ijms23169407. [PMID: 36012674 PMCID: PMC9409090 DOI: 10.3390/ijms23169407] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetic kidney disease (DKD) can cause inflammation and fibrosis, in addition to being the main complication of diabetes. Among many factors, epigenetic alterations in aberrant histone modifications play a key role in causing DKD. In this study, the mechanism of GSK-J4, a histone demethylase KDM6A inhibitor, was evaluated in streptozotocin-induced diabetic mice. It was confirmed that GSK-J4, via dickkopf-1 (DKK1) modulation, could significantly reduce proteinuria and glomerulosclerosis in diabetic mice. The mRNA accumulation levels of DKK1, TGF-β1, fibronectin, and collagen IV were significantly elevated in diabetic mice. In contrast, the mRNA accumulations of those genes were significantly reduced in diabetic mice treated with GSK-J4 compared to those in diabetic mice, relatively speaking. The protein accumulation levels of fibronectin and collagen IV were significantly elevated in diabetic mice. Furthermore, GSK-J4 attenuated the high glucose-induced expression of profibrotic factors in mesangial cells via DKK1. In conclusion, our study provides a novel strategy to eliminate fibrosis in the kidneys of DKD mice. Using GSK-J4 reduces DKK1 expression, thereby ameliorating renal insufficiency, glomerulosclerosis morphological abnormalities, inflammation, and fibrosis in diabetic mice.
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Affiliation(s)
- Peir-Haur Hung
- Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan
- Department of Applied Life Science and Health, Chia-Nan University of Pharmacy and Science, Tainan 717301, Taiwan
| | - Yung-Chien Hsu
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
| | - Tsung-Hsien Chen
- Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan
| | - Cheng Ho
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Correspondence: (C.H.); (C.-L.L.)
| | - Chun-Liang Lin
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan
- Kidney Research Center, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Chang Gung Memorial Hospital, Kaohsiung 833253, Taiwan
- Correspondence: (C.H.); (C.-L.L.)
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19
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Yamaguchi T, Yoshida K, Murata M, Suwa K, Tsuneyama K, Matsuzaki K, Naganuma M. Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis. Int J Mol Sci 2022; 23:ijms23116270. [PMID: 35682957 PMCID: PMC9181097 DOI: 10.3390/ijms23116270] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/28/2022] [Accepted: 05/29/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAFLD progression from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually end-stage liver diseases in a proportion of cases. Hepatic fibrosis and carcinogenesis often progress together, sharing inflammatory pathways. However, NASH can lead to hepatocarcinogenesis with minimal inflammation or fibrosis. In such instances, insulin resistance, oxidative stress, and lipotoxicity can directly lead to liver carcinogenesis through genetic and epigenetic alterations. Transforming growth factor (TGF)-β signaling is implicated in hepatic fibrogenesis and carcinogenesis. TGF-β type I receptor (TβRI) and activated-Ras/c-Jun-N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3 to create two phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TβRI/pSmad3C signaling terminates cell proliferation, while constitutive Ras activation and JNK-mediated pSmad3L promote hepatocyte proliferation and carcinogenesis. The pSmad3L signaling pathway also antagonizes cytostatic pSmad3C signaling. This review addresses TGF-β/Smad signaling in hepatic carcinogenesis complicating NASH. We also discuss Smad phospho-isoforms as biomarkers predicting HCC in NASH patients with or without cirrhosis.
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Affiliation(s)
- Takashi Yamaguchi
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
- Correspondence: ; Tel.: +81-72-804-0101; Fax: +81-72-804-2524
| | - Katsunori Yoshida
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Miki Murata
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Kanehiko Suwa
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Koichi Tsuneyama
- Department of Pathology & Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan;
| | - Koichi Matsuzaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Makoto Naganuma
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
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Park HB, Baek KH. E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers. Biochim Biophys Acta Rev Cancer 2022; 1877:188736. [DOI: 10.1016/j.bbcan.2022.188736] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/30/2022] [Accepted: 05/11/2022] [Indexed: 12/13/2022]
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Pan Y, Tan WF, Yang MQ, Li JY, Geller DA. The therapeutic potential of exosomes derived from different cell sources in liver diseases. Am J Physiol Gastrointest Liver Physiol 2022; 322:G397-G404. [PMID: 35107032 PMCID: PMC8917924 DOI: 10.1152/ajpgi.00054.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Exosomes are small nanovesicles with a size of approximately 40-120 nm that are secreted from cells. They are involved in the regulation of cell homeostasis and mediate intercellular communication. In addition, they carry proteins, nucleic acids, and lipids that regulate the biological activity of receptor cells. Recent studies have shown that exosomes perform important functions in liver diseases. This review will focus on liver diseases (drug-induced liver injury, hepatic ischemia-reperfusion injury, liver fibrosis, acute liver failure, and hepatocellular carcinoma) and summarize the therapeutic potential of exosomes from different cell sources in liver disease.
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Affiliation(s)
- Yun Pan
- 1Colorectal Cancer Center, Tenth People’s Hospital of Tongji University, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Wei-Feng Tan
- 2Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Mu-Qing Yang
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - Ji-Yu Li
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - David A. Geller
- 4Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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22
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Jiang H, Zhang Z, Yu Y, Chu HY, Yu S, Yao S, Zhang G, Zhang BT. Drug Discovery of DKK1 Inhibitors. Front Pharmacol 2022; 13:847387. [PMID: 35355709 PMCID: PMC8959454 DOI: 10.3389/fphar.2022.847387] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 02/21/2022] [Indexed: 12/24/2022] Open
Abstract
Dickkopf-1 (DKK1) is a well-characterized Wnt inhibitor and component of the Wnt/β-catenin signaling pathway, whose dysregulation is associated with multiple abnormal pathologies including osteoporosis, Alzheimer's disease, diabetes, and various cancers. The Wnt signaling pathway has fundamental roles in cell fate determination, cell proliferation, and survival; thus, its mis-regulation can lead to disease. Although DKK1 is involved in other signaling pathways, including the β-catenin-independent Wnt pathway and the DKK1/CKAP4 pathway, the inhibition of DKK1 to propagate Wnt/β-catenin signals has been validated as an effective way to treat related diseases. In fact, strategies for developing DKK1 inhibitors have produced encouraging clinical results in different pathological models, and many publications provide detailed information about these inhibitors, which include small molecules, antibodies, and nucleic acids, and may function at the protein or mRNA level. However, no systematic review has yet provided an overview of the various aspects of their development and prospects. Therefore, we review the DKK1 inhibitors currently available or under study and provide an outlook on future studies involving DKK1 and drug discovery.
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Affiliation(s)
- Hewen Jiang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Zongkang Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Yuanyuan Yu
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China.,Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.,Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Hang Yin Chu
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Sifan Yu
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China.,Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.,Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Shanshan Yao
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Ge Zhang
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China.,Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.,Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Bao-Ting Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
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23
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Li L, Wang Q, He Y, Sun L, Yang Y, Pang X. Astragaloside IV suppresses migration and invasion of TGF-β 1-induced human hepatoma HuH-7 cells by regulating Nrf2/HO-1 and TGF-β 1/Smad3 pathways. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:397-405. [PMID: 35092472 DOI: 10.1007/s00210-021-02199-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/23/2021] [Indexed: 11/30/2022]
Abstract
Astragaloside IV (AS-IV), one of the major compounds extract from Astragalus membranaceus, has shown attractive anti-cancer effects in certain malignancies. Oxidative stress (OS) is considered as a crucial factor in promoting the progression of hepatocellular carcinoma (HCC). In response to OS, nuclear factor erythroid 2-related factor 2 (Nrf2) upregulates and induces heme oxygenase 1 (HO-1) to combat oxidative damages. The phosphorylation of the COOH-terminal of Smad3 (pSmad3C) activates p21 to resist HCC progression, while the phosphorylation of the linker region of Smad3 (pSmad3L) up-regulates c-Myc transcription to exert promoting effect towards HCC. This study aimed to explore whether AS-IV suppresses migration and invasion of human hepatoma HuH-7 cells by regulating Nrf2/HO-1 and TGF-β1/Smad3 pathways. HuH-7 cells were induced with TGF-β1 (9 or 40 pM) to establish HCC model in vitro and pretreated with AS-IV at different concentration (5, 10, and 20 μM) for 24 h. Cell proliferation, migration, invasion, and intracellular reactive oxygen species (ROS) of HuH-7 cells were measured. The expression of Nrf2, pSmad3C, Nrf2/pNrf2, HO-1, pSmad3C/3L, c-Myc, and p21 were detected. Exposure of HuH-7 cells to TGF-β1 enhanced the cell proliferation, migration, invasion, and ROS production. Pretreatment with AS-IV (5, 10, and 20 μM) significantly reduced the cell proliferation, migration, invasion, and ROS production in HuH-7 cells. Furthermore, AS-IV increased the expressions of Nrf2/pNrf2, HO-1, pSmad3C, and p21, meanwhile reduced the expressions of pSmad3L and c-Myc. In conclusion, our study suggested that AS-IV inhibit HuH-7 cells migration and invasion, which related to activate Nrf2/HO-1 pathway, up-regulation pSmad3C/p21 pathway, and down-regulation pSmad3L/c-Myc pathway. The present research supports the notion that AS-IV may be a latent agent for the treatment of HCC.
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Affiliation(s)
- Lili Li
- Department of Pharmacology, Key Laboratory of Anti-Inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China
| | - Qin Wang
- Department of Pharmacology, Key Laboratory of Anti-Inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China
| | - Yinghao He
- Department of Pharmacology, Key Laboratory of Anti-Inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China
| | - Liangjie Sun
- Department of Pharmacology, Key Laboratory of Anti-Inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China
| | - Yan Yang
- Department of Pharmacology, Key Laboratory of Anti-Inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China.
| | - Xiaonan Pang
- Department of Pharmacology, Key Laboratory of Anti-Inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China.
- Department of Oncology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
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24
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Presence of CrkI-containing microvesicles in squamous cell carcinomas could have ramifications on tumor biology and cancer therapeutics. Sci Rep 2022; 12:4803. [PMID: 35314778 PMCID: PMC8938485 DOI: 10.1038/s41598-022-08905-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 03/15/2022] [Indexed: 11/24/2022] Open
Abstract
Recently, we described a phenomenon whereby apoptotic cells generate and release CrkI-containing microvesicles, which stimulate proliferation in surrounding cells upon contact to compensate for their own demise. We termed these microvesicles “ACPSVs” for Apoptotic Compensatory Proliferation Signaling microvesicles. As immune cells and a majority of current cancer therapeutics destroy tumor cells primarily by apoptosis, we conducted a small pilot study to assess the possibility that ACPSVs may also be generated in squamous cell carcinomas. We first evaluated a primary and a metastatic squamous cell carcinoma cancer cell lines for their ability to produce ACPSVs under normal and apoptotic conditions. We next conducted a pilot study to assess the occurrence of ACPSVs in solid tumors extracted from 20 cancer patients with squamous cell carcinomas. Both cancer cell lines produced copious amounts of ACPSVs under apoptotic conditions. Interestingly, the metastatic squamous cell carcinoma cancer cell line also produced high levels of ACPSVs under healthy condition, suggesting that the ability to generate ACPSVs may be hijacked by these cells. Importantly, ACPSVs were also abundant in the solid tumors of all squamous cell carcinoma cancer patients. Detection of ACPSVs in cancer has potentially important ramifications in tumor biology and cancer therapeutics which warrants further investigation.
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25
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Hepatitis C virus (HCV)-induced ROS/JNK signaling pathway activates the E3 ubiquitin ligase Itch to promote the release of HCV particles via polyubiquitylation of VPS4A. J Virol 2022; 96:e0181121. [PMID: 35044214 DOI: 10.1128/jvi.01811-21] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We previously reported that hepatitis C virus (HCV) infection activates the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) signaling pathway. However, the roles of ROS/JNK activation in the HCV life cycle still remain unclear. We sought to identify a novel role of ROS/JNK signaling pathway in the HCV life cycle. Immunoblot analysis revealed that HCV-induced ROS/JNK activation promoted phosphorylation of Itch, a HECT-type E3 ubiquitin ligase, leading to activation of Itch. The siRNA-knockdown of Itch significantly reduced the extracellular HCV infectivity titers, HCV RNA, and HCV core protein without affecting intracellular HCV infectivity titers, HCV RNA, and HCV proteins, suggesting that Itch is involved in release of HCV particles. HCV-mediated JNK/Itch activation specifically promoted polyubiquitylation of an AAA-type ATPase VPS4A, but not VPS4B, required to form multivesicular bodies. Site-directed mutagenesis revealed that two lysine residues (K23 and K121) on VPS4A were important for VPS4A polyubiquitylation. The siRNA-knockdown of VPS4A, but not VPS4B, significantly reduced extracellular HCV infectivity titers. Co-immunoprecipitation analysis revealed that HCV infection specifically enhanced the interaction between CHMP1B, a subunit of endosomal sorting complexes required for transport (ESCRT)-III complex, and VPS4A, but not VPS4B, whereas VPS4A K23R/K121R greatly reduced the interaction with CHMP1B. HCV infection significantly increased ATPase activity of VPS4A, but not VPS4A K23R/K121R or VPS4B, suggesting that HCV-mediated polyubiquitylation of VPS4A contributes to activation of VPS4A. Taken together, we propose that HCV-induced ROS/JNK/Itch signaling pathway promotes VPS4A polyubiquitylation, leading to enhanced VPS4A-CHMP1B interaction and promotion of VPS4A ATPase activity, thereby promoting the release of HCV particles. IMPORTANCE ROS/JNK signaling pathway contributes to liver diseases, including steatosis, metabolic disorders, and hepatocellular carcinoma. We previously reported that HCV activates the ROS/JNK signaling pathway, leading to the enhancement of hepatic gluconeogenesis and apoptosis induction. This study further demonstrates that HCV-induced ROS/JNK signaling pathway activates the E3 ubiquitin ligase Itch to promote release of HCV particles via polyubiquitylation of VPS4A. We provide evidence suggesting that HCV infection promotes the ROS/JNK/Itch signaling pathway and ESCRT/VPS4A machinery to release infectious HCV particles. Our results may lead to a better understanding of the mechanistic details of HCV particle release.
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26
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Mahapatra S, Mohanty S, Mishra R, Prasad P. An overview of cancer and the human microbiome. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2022; 191:83-139. [DOI: 10.1016/bs.pmbts.2022.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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27
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Helmrich N, Roderfeld M, Baier A, Windhorst A, Herebian D, Mayatepek E, Dierkes C, Ocker M, Glebe D, Christ B, Churin Y, Irungbam K, Roeb E. Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4 -/- Mice. Cell Mol Gastroenterol Hepatol 2021; 13:1041-1055. [PMID: 34954190 PMCID: PMC8873597 DOI: 10.1016/j.jcmgh.2021.12.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 11/26/2021] [Accepted: 12/14/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS The endocannabinoid system is involved in the modulation of inflammatory, fibrotic, metabolic, and carcinogenesis-associated signaling pathways via cannabinoid receptor (CB)1 and CB2. We hypothesized that the pharmacologic antagonization of CB1 receptor improves cholestasis in Abcb4-/- mice. METHODS After weaning, male Abcb4-/- mice were treated orally with rimonabant (a specific antagonist of CB1) or ACEA (an agonist of CB1) until up to 16 weeks of age. Liver tissue and serum were isolated and examined by means of serum analysis, quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and enzyme function. Untreated Abcb4-/- and Bagg Albino Mouse/c wild-type mice served as controls. RESULTS Cholestasis-induced symptoms such as liver damage, bile duct proliferation, and enhanced circulating bile acids were improved by CB1 antagonization. Rimonabant treatment also improved Phosphoenolpyruvat-Carboxykinase expression and reduced inflammation and the acute-phase response. The carcinogenesis-associated cellular-Jun N-terminal kinase/cellular-JUN and signal transducer and activator of transcription 3 signaling pathways activated in Abcb4-/- mice were reduced to wild-type level by CB1 antagonization. CONCLUSIONS We showed a protective effect of oral CB1 antagonization in chronic cholestasis using the established Abcb4-/- model. Our results suggest that pharmacologic antagonization of the CB1 receptor could have a therapeutic benefit in cholestasis-associated metabolic changes, liver damage, inflammation, and carcinogenesis.
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Affiliation(s)
| | | | - Anne Baier
- Department of Gastroenterology, Giessen, Germany
| | - Anita Windhorst
- Institute for Medical Informatics, Justus Liebig University, Giessen, Germany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Christian Dierkes
- Medizinisches Versorgungszentrum for Pathology, Justus Liebig University Giessen, Trier, Germany
| | - Matthias Ocker
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University, Giessen, Germany
| | - Bruno Christ
- Applied Molecular Hepatology Laboratory, Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, Leipzig, Germany
| | - Yuri Churin
- Department of Gastroenterology, Giessen, Germany
| | | | - Elke Roeb
- Department of Gastroenterology, Giessen, Germany,Correspondence Address correspondence to: Elke Roeb, MD, MHAC, Department of Gastroenterology, Justus Liebig University Giessen, University Hospital Universitätsklinikum Giessen und Marburg (UKGM), Klinikstrasse 33, 35392 Giessen, Germany. fax: (49) 641-985-42339.
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28
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Why may citrate sodium significantly increase the effectiveness of transarterial chemoembolization in hepatocellular carcinoma? Drug Resist Updat 2021; 59:100790. [PMID: 34924279 DOI: 10.1016/j.drup.2021.100790] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/01/2021] [Accepted: 09/04/2021] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) represents the third cause of cancer death in men worldwide, and its increasing incidence can be explained by the increasing occurrence of non-alcoholic steatohepatitis (NASH). HCC prognosis is poor, as its 5-year overall survival is approximately 18 % and most cases are diagnosed at an inoperable advanced stage. Moreover, tumor sensitivity to conventional chemotherapeutics (particularly to cisplatin-based regimen), trans-arterial chemoembolization (cTACE), tyrosine kinase inhibitors, anti-angiogenic molecules and immune checkpoint inhibitors is limited. Oncogenic signaling pathways, such as HIF-1α and RAS/PI3K/AKT, may provoke drug resistance by enhancing the aerobic glycolysis ("Warburg effect") in cancer cells. Indeed, this metabolism, which promotes cancer cell development and aggressiveness, also induces extracellular acidity. In turn, this acidity promotes the protonation of drugs, hence abrogating their internalization, since they are most often weakly basic molecules. Consequently, targeting the Warburg effect in these cancer cells (which in turn would reduce the extracellular acidification) could be an effective strategy to increase the delivery of drugs into the tumor. Phosphofructokinase-1 (PFK1) and its activator PFK2 are the main regulators of glycolysis, and they also couple the enhancement of glycolysis to the activation of key signaling cascades and cell cycle progression. Therefore, targeting this "Gordian Knot" in HCC cells would be of crucial importance. Here, we suggest that this could be achieved by citrate administration at high concentration, because citrate is a physiologic inhibitor of PFK1 and PFK2. As shown in various in vitro studies, including HCC cell lines, administration of high concentrations of citrate inhibits PFK1 and PFK2 (and consequently glycolysis), decreases ATP production, counteracts HIF-1α and PI3K/AKT signaling, induces apoptosis, and sensitizes cells to cisplatin treatment. Administration of high concentrations of citrate in animal models (including Ras-driven tumours) has been shown to effectively inhibit cancer growth, reverse cell dedifferentiation, and neutralize intratumor acidity, without apparent toxicity in animal studies. Citrate may also induce a rapid secretion of pro-inflammatory cytokines by macrophages, and it could favour the destruction of cancer stem cells (CSCs) sustaining tumor recurrence. Consequently, this "citrate strategy" could improve the tumor sensitivity to current treatments of HCC by reducing the extracellular acidity, thus enhancing the delivery of chemotherapeutic drugs into the tumor. Therefore, we propose that this strategy should be explored in clinical trials, in particular to enhance cTACE effectiveness.
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29
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Correia de Sousa M, Calo N, Sobolewski C, Gjorgjieva M, Clément S, Maeder C, Dolicka D, Fournier M, Vinet L, Montet X, Dufour JF, Humar B, Negro F, Sempoux C, Foti M. Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis. Cancers (Basel) 2021; 13:4983. [PMID: 34638467 PMCID: PMC8508272 DOI: 10.3390/cancers13194983] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/28/2021] [Accepted: 09/28/2021] [Indexed: 12/14/2022] Open
Abstract
The microRNA 21 (miR-21) is upregulated in almost all known human cancers and is considered a highly potent oncogene and potential therapeutic target for cancer treatment. In the liver, miR-21 was reported to promote hepatic steatosis and inflammation, but whether miR-21 also drives hepatocarcinogenesis remains poorly investigated in vivo. Here we show using both carcinogen (Diethylnitrosamine, DEN) or genetically (PTEN deficiency)-induced mouse models of hepatocellular carcinoma (HCC), total or hepatocyte-specific genetic deletion of this microRNA fosters HCC development-contrasting the expected oncogenic role of miR-21. Gene and protein expression analyses of mouse liver tissues further indicate that total or hepatocyte-specific miR-21 deficiency is associated with an increased expression of oncogenes such as Cdc25a, subtle deregulations of the MAPK, HiPPO, and STAT3 signaling pathways, as well as alterations of the inflammatory/immune anti-tumoral responses in the liver. Together, our data show that miR-21 deficiency promotes a pro-tumoral microenvironment, which over time fosters HCC development via pleiotropic and complex mechanisms. These results question the current dogma of miR-21 being a potent oncomiR in the liver and call for cautiousness when considering miR-21 inhibition for therapeutic purposes in HCC.
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Affiliation(s)
- Marta Correia de Sousa
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.C.d.S.); (N.C.); (C.S.); (M.G.); (C.M.); (D.D.); (M.F.)
| | - Nicolas Calo
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.C.d.S.); (N.C.); (C.S.); (M.G.); (C.M.); (D.D.); (M.F.)
| | - Cyril Sobolewski
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.C.d.S.); (N.C.); (C.S.); (M.G.); (C.M.); (D.D.); (M.F.)
| | - Monika Gjorgjieva
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.C.d.S.); (N.C.); (C.S.); (M.G.); (C.M.); (D.D.); (M.F.)
| | - Sophie Clément
- Division of Clinical Pathology, Geneva University Hospitals, 1206 Geneva, Switzerland; (S.C.); (F.N.)
| | - Christine Maeder
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.C.d.S.); (N.C.); (C.S.); (M.G.); (C.M.); (D.D.); (M.F.)
| | - Dobrochna Dolicka
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.C.d.S.); (N.C.); (C.S.); (M.G.); (C.M.); (D.D.); (M.F.)
| | - Margot Fournier
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.C.d.S.); (N.C.); (C.S.); (M.G.); (C.M.); (D.D.); (M.F.)
| | - Laurent Vinet
- Department of Radiology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (L.V.); (X.M.)
| | - Xavier Montet
- Department of Radiology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (L.V.); (X.M.)
| | - Jean-François Dufour
- Department for Visceral Surgery and Medicine, University Hospital Bern, 3010 Bern, Switzerland;
| | - Bostjan Humar
- Department of Visceral & Transplantation Surgery, University Hospital Zürich, 8006 Zürich, Switzerland;
| | - Francesco Negro
- Division of Clinical Pathology, Geneva University Hospitals, 1206 Geneva, Switzerland; (S.C.); (F.N.)
| | - Christine Sempoux
- Service of Clinical Pathology, University Institute of Pathology, Vaud University Hospital Center, 1011 Lausanne, Switzerland;
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; (M.C.d.S.); (N.C.); (C.S.); (M.G.); (C.M.); (D.D.); (M.F.)
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30
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Traub B, Roth A, Kornmann M, Knippschild U, Bischof J. Stress-activated kinases as therapeutic targets in pancreatic cancer. World J Gastroenterol 2021; 27:4963-4984. [PMID: 34497429 PMCID: PMC8384741 DOI: 10.3748/wjg.v27.i30.4963] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/17/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving in vivo investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.
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Affiliation(s)
- Benno Traub
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Aileen Roth
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Marko Kornmann
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Uwe Knippschild
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Joachim Bischof
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
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31
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Sun L, Patai ÁV, Hogenson TL, Fernandez-Zapico ME, Qin B, Sinicrope FA. Irreversible JNK blockade overcomes PD-L1-mediated resistance to chemotherapy in colorectal cancer. Oncogene 2021; 40:5105-5115. [PMID: 34193942 DOI: 10.1038/s41388-021-01910-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 11/09/2022]
Abstract
Colorectal cancer (CRC) cells have low or absent tumor cell PD-L1 expression that we previously demonstrated can confer chemotherapy resistance. Here, we demonstrate that PD-L1 depletion enhances JNK activity resulting in increased BimThr116 phosphorylation and its sequestration by MCL-1 and BCL-2. Activated JNK signaling in PD-L1-depeted cells was due to reduced mRNA stability of the CYLD deubiquitinase. PD-L1 was found to compete with the ribonuclease EXOSC10 for binding to CYLD mRNA. Thus, loss of PD-L1 promoted binding and degradation of CYLD mRNA by EXOSC10 which enhanced JNK activity. An irreversible JNK inhibitor (JNK-IN-8) reduced BimThr116 phosphorylation and unsequestered Bim from MCL-1 and BCL-2 to promote apoptosis. In cells lacking PD-L1, treatment with JNK-IN-8, an MCL-1 antagonist (AZD5991), or their combination promoted apoptosis and reduced long-term clonogenic survival by anticancer drugs. Similar effects of the JNK inhibitor on cell viability were observed in CRC organoids with suppression of PD-L1. These data indicate that JNK inhibition may represent a promising strategy to overcome drug resistance in CRC cells with low or absent PD-L1 expression.
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Affiliation(s)
- Lei Sun
- Gastrointestinal Research Unit, Mayo Clinic, Rochester, MN, USA.,Department of Gastrointestinal Surgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Árpád V Patai
- Gastrointestinal Research Unit, Mayo Clinic, Rochester, MN, USA
| | - Tara L Hogenson
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Martin E Fernandez-Zapico
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Bo Qin
- Gastrointestinal Research Unit, Mayo Clinic, Rochester, MN, USA.
| | - Frank A Sinicrope
- Gastrointestinal Research Unit, Mayo Clinic, Rochester, MN, USA. .,Departments of Medicine and Oncology, Mayo Clinic, Rochester, MN, USA. .,Mayo Comprehensive Cancer Center, Rochester, MN, USA.
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Ooshio T, Yamamoto M, Fujii K, Xin B, Watanabe K, Goto M, Okada Y, Suzuki A, Penninger JM, Nishina H, Nishikawa Y. Hepatocyte Mitogen-Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice. Hepatology 2021; 73:2510-2526. [PMID: 32969030 PMCID: PMC8252741 DOI: 10.1002/hep.31565] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 08/14/2020] [Accepted: 09/02/2020] [Indexed: 01/23/2023]
Abstract
BACKGROUND AND AIMS Mitogen-activated protein kinase kinase (MKK) 7 and MKK4 are upstream activators of c-Jun NH2 -terminal kinases (JNKs) and have been shown to be required for the early development of the liver. Although it has been suggested that MKK7 might be involved in the regulation of hepatocyte proliferation, the functional role of MKK7 in the liver has remained unclear. APPROACH AND RESULTS Here, we examined phenotypic alterations in liver-specific or hepatocyte/hematopoietic cell-specific MKK7 knockout (KO) mice, which were generated by crossing MKK7LoxP/LoxP with albumin-cyclization recombination (Alb-Cre) or myxovirus resistance protein 1-Cre mice, respectively. The livers of Alb-Cre-/+ MKK7LoxP/LoxP mice developed without discernible tissue disorganization. MKK7 KO mice responded normally to liver injuries incurred by partial hepatectomy or injection of CCl4 . However, tissue repair following CCl4 -induced injury was delayed in MKK7 KO mice compared with that of control mice. Furthermore, after repeated injections of CCl4 for 8 weeks, the liver in MKK7 KO mice showed intense fibrosis with increased protractive hepatocyte proliferation, suggesting that MKK7 deficiency might affect regenerative responses of hepatocytes in the altered tissue microenvironment. MKK7 KO hepatocytes demonstrated normal proliferative activity when cultured in monolayers. However, MKK7 KO significantly suppressed branching morphogenesis of hepatocyte aggregates within a collagen gel matrix. Microarray analyses revealed that suppression of branching morphogenesis in MKK7 KO hepatocytes was associated with a reduction in mRNA expression of transgelin, glioma pathogenesis related 2, and plasminogen activator urokinase-type (Plau); and forced expression of these genes in MKK7 KO hepatocytes partially recovered the attenuated morphogenesis. Furthermore, hepatocyte-specific overexpression of Plau rescued the impaired tissue repair of MKK7 KO mice following CCl4 -induced injury. CONCLUSIONS MKK7 is dispensable for the regenerative proliferation of hepatocytes but plays important roles in repair processes following parenchymal destruction, possibly through modulation of hepatocyte-extracellular matrix interactions.
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Affiliation(s)
- Takako Ooshio
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Masahiro Yamamoto
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Kiyonaga Fujii
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Bing Xin
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Kenji Watanabe
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan,Division of Gastroenterological and General SurgeryDepartment of SurgeryAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Masanori Goto
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Yoko Okada
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
| | - Akira Suzuki
- Division of Molecular and Cellular BiologyKobe University Graduate School of MedicineKobeHyogoJapan
| | - Josef M. Penninger
- Department of Medical GeneticsLife Sciences InstituteUniversity of British ColumbiaVancouverBCCanada,Institute of Molecular Biotechnology of the Austrian Academy of SciencesViennaAustria
| | - Hiroshi Nishina
- Department of Developmental and Regenerative BiologyMedical Research InstituteTokyo Medical and Dental UniversityBunkyo‐ku, TokyoJapan
| | - Yuji Nishikawa
- Division of Tumor PathologyDepartment of PathologyAsahikawa Medical UniversityAsahikawaHokkaidoJapan
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JNK signaling as a target for anticancer therapy. Pharmacol Rep 2021; 73:405-434. [PMID: 33710509 DOI: 10.1007/s43440-021-00238-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/30/2021] [Accepted: 02/15/2021] [Indexed: 12/15/2022]
Abstract
The JNKs are members of mitogen-activated protein kinases (MAPK) which regulate many physiological processes including inflammatory responses, macrophages, cell proliferation, differentiation, survival, and death. It is increasingly clear that the continuous activation of JNKs has a role in cancer development and progression. Therefore, JNKs represent attractive oncogenic targets for cancer therapy using small molecule kinase inhibitors. Studies showed that the two major JNK proteins JNK1 and JNK2 have opposite functions in different types of cancers, which need more specification in the design of JNK inhibitors. Some of ATP- competitive and ATP non-competitive inhibitors have been developed and widely used in vitro, but this type of inhibitors lack selectivity and inhibits phosphorylation of all JNK substrates and may lead to cellular toxicity. In this review, we summarized and discussed the strategies of JNK binding inhibitors and the role of JNK signaling in the pathogenesis of different solid and hematological malignancies.
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Cicuéndez B, Ruiz-Garrido I, Mora A, Sabio G. Stress kinases in the development of liver steatosis and hepatocellular carcinoma. Mol Metab 2021; 50:101190. [PMID: 33588102 PMCID: PMC8324677 DOI: 10.1016/j.molmet.2021.101190] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/31/2020] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an important component of metabolic syndrome and one of the most prevalent liver diseases worldwide. This disorder is closely linked to hepatic insulin resistance, lipotoxicity, and inflammation. Although the mechanisms that cause steatosis and chronic liver injury in NAFLD remain unclear, a key component of this process is the activation of stress-activated kinases (SAPKs), including p38 and JNK in the liver and immune system. This review summarizes findings which indicate that the dysregulation of stress kinases plays a fundamental role in the development of steatosis and are important players in inducing liver fibrosis. To avoid the development of steatohepatitis and liver cancer, SAPK activity must be tightly regulated not only in the hepatocytes but also in other tissues, including cells of the immune system. Possible cellular mechanisms of SAPK actions are discussed.
Hepatic JNK triggers steatosis and insulin resistance, decreasing lipid oxidation and ketogenesis in HFD-fed mice. Decreased liver expression of p38α/β in HFD increases lipogenesis. Hepatic p38γ/δ drive insulin resistance and inhibit autophagy, which may lead to steatosis. Macrophage p38α/β promote cytokine production and M1 polarization, leading to lipid accumulation in hepatocytes. Myeloid p38γ/δ contribute to cytokine production and neutrophil migration, protecting against steatosis, diabetes and NAFLD. JNK1 and p38γ induce HCC while p38α blocks it. However, deletion of hepatic JNK1/2 induces cholangiocarcinoma. SAPK are potential therapeutic target for metabolic disorders, steatohepatitis and liver cancer.
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Affiliation(s)
- Beatriz Cicuéndez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Irene Ruiz-Garrido
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Alfonso Mora
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
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Desideri E, Ciriolo MR. Inhibition of JNK increases the sensitivity of hepatocellular carcinoma cells to lysosomotropic drugs via LAMP2A destabilization. Cell Death Discov 2021; 7:29. [PMID: 33558496 PMCID: PMC7870977 DOI: 10.1038/s41420-021-00408-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/23/2020] [Accepted: 01/09/2021] [Indexed: 12/21/2022] Open
Abstract
Alteration of lysosomal homeostasis is common in cancer cells, which often feature an enlarged and peripheral distributed lysosomal compartment and the overexpression of cathepsins. These alterations accelerate the production of building blocks for the de novo synthesis of macromolecules and contribute to the degradation of the extracellular matrix, thus contributing to tumor growth and invasion. At the same time, they make lysosomes more fragile and more prone to lysosomal membrane permeabilization, a condition that can cause the release of proteases into the cytosol and the activation of cell death. Therefore, lysosomes represent a weak spot of cancer cells that can be targeted for therapeutic purposes. Here, we identify a novel role of the kinase JNK as keeper of lysosomal stability in hepatocellular carcinoma cells. JNK inhibition reduces the stability of LAMP2A, a lysosomal membrane protein responsible for the stability of the lysosomal membrane, promoting its degradation by the proteasome. LAMP2A decrease enhances the lysosomal damage induced by lysosomotropic agents, ultimately leading to cell death. The effect is cancer-specific, as JNK inhibition does not decrease LAMP2A in non-tumoral liver cells and does not alter their sensitivity to lysosomotropic drugs. Our finding on the new role of JNK as cancer-specific keeper of lysosomal homeostasis lays the ground for future evaluation of the efficacy of the combination of JNK inhibition and lysosomotropic agents as a potential therapeutic strategy in hepatocellular carcinoma.
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Affiliation(s)
- Enrico Desideri
- Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy.
| | - Maria Rosa Ciriolo
- Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy. .,IRCCS San Raffaele Pisana, Via della Pisana 235, 00163, Rome, Italy.
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Poothong J, Jang I, Kaufman RJ. Defects in Protein Folding and/or Quality Control Cause Protein Aggregation in the Endoplasmic Reticulum. PROGRESS IN MOLECULAR AND SUBCELLULAR BIOLOGY 2021; 59:115-143. [PMID: 34050864 DOI: 10.1007/978-3-030-67696-4_6] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Protein aggregation is now a common hallmark of numerous human diseases, most of which involve cytosolic aggregates including Aβ (AD) and ⍺-synuclein (PD) in Alzheimer's disease and Parkinson's disease. However, it is also evident that protein aggregation can also occur in the lumen of the endoplasmic reticulum (ER) that leads to specific diseases due to loss of protein function or detrimental effects on the host cell, the former is inherited in a recessive manner where the latter are dominantly inherited. However, the mechanisms of protein aggregation, disaggregation and degradation in the ER are not well understood. Here we provide an overview of factors that cause protein aggregation in the ER and how the ER handles aggregated proteins. Protein aggregation in the ER can result from intrinsic properties of the protein (hydrophobic residues in the ER), oxidative stress or nutrient depletion. The ER has quality control mechanisms [chaperone functions, ER-associated protein degradation (ERAD) and autophagy] to ensure only correctly folded proteins exit the ER and enter the cis-Golgi compartment. Perturbation of protein folding in the ER activates the unfolded protein response (UPR) that evolved to increase ER protein folding capacity and efficiency and degrade misfolded proteins. Accumulation of misfolded proteins in the ER to a level that exceeds the ER-chaperone folding capacity is a major factor that exacerbates protein aggregation. The most significant ER resident protein that prevents protein aggregation in the ER is the heat shock protein 70 (HSP70) homologue, BiP/GRP78, which is a peptide-dependent ATPase that binds unfolded/misfolded proteins and releases them upon ATP binding. Since exogenous factors can also reduce protein misfolding and aggregation in the ER, such as chemical chaperones and antioxidants, these treatments have potential therapeutic benefit for ER protein aggregation-associated diseases.
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Affiliation(s)
- Juthakorn Poothong
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Insook Jang
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Randal J Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
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Abstract
Obesity is a health condition that has reached pandemic levels and is implicated in the development and progression of type 2 diabetes mellitus, cancer and heart failure. A key characteristic of obesity is the activation of stress-activated protein kinases (SAPKs), such as the p38 and JNK stress kinases, in several organs, including adipose tissue, liver, skeletal muscle, immune organs and the central nervous system. The correct timing, intensity and duration of SAPK activation contributes to cellular metabolic adaptation. By contrast, uncontrolled SAPK activation has been proposed to contribute to the complications of obesity. The stress kinase signalling pathways have therefore been identified as potential targets for the development of novel therapeutic approaches for metabolic syndrome. The past few decades have seen intense research efforts to determine how these kinases are regulated in a cell-specific manner and to define their contribution to the development of obesity and insulin resistance. Several studies have uncovered new and unexpected functions of the non-classical members of both pathways. Here, we provide an overview of the role of SAPKs in metabolic control and highlight important discoveries in the field.
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Affiliation(s)
- Ivana Nikolic
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Magdalena Leiva
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
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Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer related mortality with a 10 year survival rate of merely 22-35%. Tumorigenesis frequently occurs in patients with chronic liver disease where continued liver cell damage, compensatory proliferation and inflammation provide the basis for tumor initiation, promotion and progression. Animal models of HCC are particularly useful to better understand molecular events underlying liver tumorigenesis. To this end, chemical carcinogenesis protocols based on the injection of genotoxic compounds such as diethylnitrosamine (DEN) are widely used to model liver tumorigenesis in rodents. DEN injection into 2 week old mice is sufficient to cause liver tumorigenesis after 8-10 months. When injected into older mice, DEN has to be combined with administration of tumor promoting agents such as phenobarbital or feeding high fat diet. Such protocols allow to dissect the different steps of tumor formation (i.e., tumor initiation and promotion) experimentally and to model liver pathologies in mice which frequently lead to HCC in human patients such as non-alcoholic fatty liver disease. Here, we review several established chemical carcinogenesis protocols based on DEN injection into mice and discuss their advantages as well as potential limitations.
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Affiliation(s)
- Isabel Schulien
- Department of Medicine II, Medical Center-University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Peter Hasselblatt
- Department of Medicine II, Medical Center-University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany.
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Targeting Signaling Pathways in Inflammatory Breast Cancer. Cancers (Basel) 2020; 12:cancers12092479. [PMID: 32883032 PMCID: PMC7563157 DOI: 10.3390/cancers12092479] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/24/2020] [Accepted: 08/28/2020] [Indexed: 12/17/2022] Open
Abstract
Inflammatory breast cancer (IBC), although rare, is the most aggressive type of breast cancer. Only 2-4% of breast cancer cases are classified as IBC, but-owing to its high rate of metastasis and poor prognosis-8% to 10% of breast cancer-related mortality occur in patients with IBC. Currently, IBC-specific targeted therapies are not available, and there is a critical need for novel therapies derived via understanding novel targets. In this review, we summarize the biological functions of critical signaling pathways in the progression of IBC and the preclinical and clinical studies of targeting these pathways in IBC. We also discuss studies of crosstalk between several signaling pathways and the IBC tumor microenvironment.
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Arfianti A, Pok S, Barn V, Haigh WG, Yeh MM, Ioannou GN, Teoh NCH, Farrell GC. Exercise retards hepatocarcinogenesis in obese mice independently of weight control. J Hepatol 2020; 73:140-148. [PMID: 32302728 DOI: 10.1016/j.jhep.2020.02.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 02/04/2020] [Accepted: 02/06/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Obesity and type 2 diabetes increase hepatocellular carcinoma (HCC) incidence in humans and accelerate diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. We investigated whether exercise reduces HCC development in obese/diabetic Alms1 mutant (foz/foz) mice and studied protective mechanisms. METHODS We measured HCC development in DEN-injected male foz/foz and wild-type (WT) littermates housed with or without an exercise wheel from week 4 until 12 or 24 weeks, and in foz/foz mice pair-fed to WT littermates. We also studied HCC development in DEN-injected Jnk1-/-.foz/foz mice generated by cross breeding, as well as their genetic controls. Dysplastic hepatocytes were identified by glutathione-S-transferase pi form (GST-pi) immunohistochemistry, liver nodules were counted, and HCC was analysed by histopathology. RESULTS Exercising foz/foz mice maintained similar weight as WT mice up to 10 weeks, but then gained weight and were obese by 24 weeks; a similar body weight profile was obtained by pair-feeding foz/foz mice to WT. At 12 weeks, livers of exercising foz/foz mice exhibited fewer GST-pi positive hepatocytes than sedentary counterparts; by 24 weeks, fewer exercising foz/foz mice developed HCC (15% vs. 64%, p <0.05). Conversely, pair-feeding foz/foz mice failed to reduce HCC incidence. In these insulin-resistant foz/foz mice, exercise failed to activate hepatic AMPK or Akt/mTORC1. Instead, it improved insulin sensitivity, ameliorated steatosis and liver injury, activated p53 to increase p27 expression, and prevented JNK activation. This was associated with suppression of hepatocellular proliferation. DEN-injected Jnk1-/-.foz/foz mice failed to develop liver tumours or HCC at 24 weeks. CONCLUSIONS Direct effects of exercise dampen proliferation of dysplastic hepatocytes to reduce 3-month dysplastic foci and 6-month incidence of DEN-induced HCC in obese, insulin-resistant mice. The effects of exercise that potentially slow hepatocarcinogenesis include p53-mediated induction of p27 and prevention of JNK activation. LAY SUMMARY Fatty liver disease commonly occurs alongside obesity and diabetes, contributing to rapidly increasing rates of liver cancer throughout the world. Herein, we show that exercise reduces the incidence and progression of hepatocellular carcinoma in mouse models. The effect of exercise on cancer risk was shown to be independent of changes in weight. Exercise could be a protective mechanism against liver cancer in at-risk individuals.
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Affiliation(s)
- Arfianti Arfianti
- Liver Research Group, ANU Medical School, Australian National University at The Canberra Hospital, Garran, ACT, Australia; Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
| | - Sharon Pok
- Liver Research Group, ANU Medical School, Australian National University at The Canberra Hospital, Garran, ACT, Australia
| | - Vanessa Barn
- Liver Research Group, ANU Medical School, Australian National University at The Canberra Hospital, Garran, ACT, Australia
| | - W Geoffrey Haigh
- Division of Gastroenterology and Hepatology, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA
| | - Matthew M Yeh
- Department of Pathology, University of Washington, Seattle, WA
| | - George N Ioannou
- Division of Gastroenterology and Hepatology, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA
| | - Narci C-H Teoh
- Liver Research Group, ANU Medical School, Australian National University at The Canberra Hospital, Garran, ACT, Australia
| | - Geoffrey C Farrell
- Liver Research Group, ANU Medical School, Australian National University at The Canberra Hospital, Garran, ACT, Australia.
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Mossenta M, Busato D, Dal Bo M, Toffoli G. Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies. Cancers (Basel) 2020; 12:E1668. [PMID: 32585931 PMCID: PMC7352479 DOI: 10.3390/cancers12061668] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/12/2020] [Accepted: 06/20/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further increase in reactive oxygen species (ROS), which could lead to cell death. HCC overcomes the problem generated by ROS increase by increasing the antioxidant machinery, in which key mechanisms involve glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible transcription factor (HIF-1α). These mechanisms could represent optimal targets for innovative therapies. The tumor microenvironment (TME) exerts a key role in HCC pathogenesis and progression. Various metabolic machineries modulate the activity of immune cells in the TME. The deregulated metabolic activity of tumor cells could impair antitumor response. Lactic acid-lactate, derived from the anaerobic glycolytic rate of tumor cells, as well as adenosine, derived from the catabolism of ATP, have an immunosuppressive activity. Metabolic reprogramming of the TME via targeted therapies could enhance the treatment efficacy of anti-cancer immunotherapy. This review describes the metabolic pathways mainly involved in the HCC pathogenesis and progression. The potential targets for HCC treatment involved in these pathways are also discussed.
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Affiliation(s)
- Monica Mossenta
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Davide Busato
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Michele Dal Bo
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
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Strauss RP, Audsley KM, Passman AM, van Vuuren JH, Finch-Edmondson ML, Callus BA, Yeoh GC. Loss of ARF/INK4A Promotes Liver Progenitor Cell Transformation Toward Tumorigenicity Supporting Their Role in Hepatocarcinogenesis. Gene Expr 2020; 20:39-52. [PMID: 32317048 PMCID: PMC7284103 DOI: 10.3727/105221620x15874935364268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Liver progenitor cells (LPCs) contribute to liver regeneration during chronic damage and are implicated as cells of origin for liver cancers including hepatocellular carcinoma (HCC). The CDKN2A locus, which encodes the tumor suppressors alternate reading frame protein (ARF) and INK4A, was identified as one of the most frequently altered genes in HCC. This study demonstrates that inactivation of CDKN2A enhances tumorigenic transformation of LPCs. The level of ARF and INK4A expression was determined in a panel of transformed and nontransformed wild-type LPC lines. Moreover, the transforming potential of LPCs with inactivated CDKN2A was shown to be enhanced in LPCs derived from Arf-/- and CDKN2Afl/fl mice and in wild-type LPCs following CRISPR-Cas9 suppression of CDKN2A. ARF and INK4A abundance is consistently reduced or ablated following LPC transformation. Arf-/- and CDKN2A-/- LPCs displayed hallmarks of transformation such as anchorage-independent and more rapid growth than control LPC lines with unaltered CDKN2A. Transformation was not immediate, suggesting that the loss of CDKN2A alone is insufficient. Further analysis revealed decreased p21 expression as well as reduced epithelial markers and increased mesenchymal markers, indicative of epithelial-to-mesenchymal transition, following inactivation of the CDKN2A gene were required for tumorigenic transformation. Loss of ARF and INK4A enhances the propensity of LPCs to undergo a tumorigenic transformation. As LPCs represent a cancer stem cell candidate, identifying CDKN2A as a driver of LPC transformation highlights ARF and INK4A as viable prognostic markers and therapeutic targets for HCC.
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Affiliation(s)
- Robyn P. Strauss
- *School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia
- †Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia
| | - Katherine M. Audsley
- *School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Adam M. Passman
- *School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia
- †Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia
| | - Joanne H. van Vuuren
- †Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia
| | | | - Bernard A. Callus
- *School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia
| | - George C. Yeoh
- *School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia
- †Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia
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Cubero FJ, Mohamed MR, Woitok MM, Zhao G, Hatting M, Nevzorova YA, Chen C, Haybaeck J, de Bruin A, Avila MA, Boekschoten MV, Davis RJ, Trautwein C. Loss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma. Hepatol Commun 2020; 4:834-851. [PMID: 32490320 PMCID: PMC7262317 DOI: 10.1002/hep4.1495] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/07/2020] [Indexed: 12/12/2022] Open
Abstract
Targeted inhibition of the c-Jun N-terminal kinases (JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)-related tumorigenesis. However, the cell-type-specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed to investigate the relevance of JNK1 and JNK2 function in hepatocytes in two different models of experimental carcinogenesis, the dethylnitrosamine (DEN) model and in nuclear factor kappa B essential modulator (NEMO)hepatocyte-specific knockout (Δhepa) mice, focusing on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development. Moreover, regulation of essential genes was assessed by reverse transcription polymerase chain reaction, immunoblottings, and immunostainings. Additionally, specific Jnk2 inhibition in hepatocytes of NEMOΔhepa/JNK1Δhepa mice was performed using small interfering (si) RNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of Jnk1 and Jnk2 in hepatocytes diminished hepatocellular carcinoma (HCC) in both the DEN model and in NEMOΔhepa mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMOΔhepa/JNK1Δhepa mice recapitulated the phenotype of NEMOΔhepa/JNKΔhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMOΔhepa mice. We found that NEMOΔhepa/JNKΔhepa livers exhibited overexpression of the interleukin-6/signal transducer and activator of transcription 3 pathway in addition to epidermal growth factor receptor (EGFR)-rapidly accelerated fibrosarcoma (Raf)-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade. The functional relevance was tested by administering lapatinib, which is a dual tyrosine kinase inhibitor of erythroblastic oncogene B-2 (ErbB2) and EGFR signaling, to NEMOΔhepa/JNKΔhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases, and effectively blocked EGFR-Raf-MEK-ERK signaling. Conclusion: We define a novel function of JNK1/2 in cholangiocyte hyperproliferation. This opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.
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Affiliation(s)
- Francisco Javier Cubero
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
- Department of Immunology, Ophthalmology, and ENTComplutense University School of MedicineMadridSpain
- 12 de Octubre Health Research InstituteMadridSpain
| | - Mohamed Ramadan Mohamed
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
- Department of Therapeutic ChemistryNational Research CenterGizaEgypt
| | - Marius M. Woitok
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
| | - Gang Zhao
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
| | - Maximilian Hatting
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
| | - Yulia A. Nevzorova
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
- Department of Genetics, Physiology, and MicrobiologyFaculty of BiologyComplutense UniversityMadridSpain
| | - Chaobo Chen
- Department of Immunology, Ophthalmology, and ENTComplutense University School of MedicineMadridSpain
| | - Johannes Haybaeck
- Department of PathologyOtto‐von‐Guericke UniversityMagdeburgGermany
- Diagnostic and Research Center for Molecular BioMedicineInstitute of PathologyMedical University of GrazGrazAustria
- Department of Pathology, Neuropathology, and Molecular PathologyMedical University of InnsbruckInnsbruckAustria
| | - Alain de Bruin
- Department of PathobiologyFaculty of Veterinary MedicineDutch Molecular Pathology CenterUtrecht UniversityUtrechtthe Netherlands
- Department of PediatricsUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Matias A. Avila
- Instituto de Investigación Sanitaria de NavarraPamplonaSpain
- Hepatology ProgramCenter for Applied Medical ResearchUniversity of NavarraPamplonaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
| | - Mark V. Boekschoten
- Nutrition, Metabolism, and Genomics GroupDivision of Human NutritionWageningen UniversityWageningenthe Netherlands
| | - Roger J. Davis
- Howard Hughes Medical InstituteUniversity of Massachusetts Medical SchoolWorcesterMA
| | - Christian Trautwein
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
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Yiqi Huoxue Recipe Improves Liver Regeneration in Rats after Partial Hepatectomy via JNK Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:9085801. [PMID: 32419833 PMCID: PMC7201470 DOI: 10.1155/2020/9085801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 03/27/2020] [Indexed: 12/16/2022]
Abstract
The liver is the only visceral organ that exhibits a remarkable capability of regenerating in response to partial hepatectomy (PH) or chemical injury. Improving liver regeneration (LR) ability is the basis for the favourable treatment outcome of patients after PH, which can serve as a potential indicator for postoperative survival. The present study aimed to investigate the protective effects of Yiqi Huoxue recipe (YQHX) on LR after PH in rats and further elucidate its underlying mechanism. A two-thirds PH rat model was used in this study. Wistar rats were randomly divided into four groups: sham-operated, PH, YQHX + PH, and Fuzheng Huayu decoction (FZHY) + PH groups. All rats were sacrificed under anesthesia at 24 and 72 h after surgery. The rates of LR were calculated, and the expression levels of cyclin D1 and c-jun were determined by immunohistochemical staining. The protein levels of p-JNK1/2, JNK1/2, p-c-jun, c-jun, Bax, and Bcl-2 were detected by Western blotting, while the mRNA levels of JNK1, JNK2, c-jun, Bax, and Bcl-2 were examined by real-time polymerase chain reaction (RT-PCR). At the corresponding time points, YQHX and FZHY administration dramatically induced the protein levels of p-JNK1/2 compared to the PH group (p < 0.05), while FZHY + PH group showed prominently increase in p-JNK1/2 protein levels compared to the YQHX + PH group (p < 0.05). A similar trend was observed for the expression levels of p-c-jun. Compared to the PH group, YQHX and FZHY markedly reduced the mRNA and protein expression levels of Bax at 24 h after PH, while those in the FZHY + PH group decreased more obviously (p < 0.05). Besides, in comparison with the PH group, YQHX and FZHY administration predominantly upregulated the mRNA and protein expression levels of Bcl-2 at 24 and 72 h after PH (p < 0.05). In conclusion, YQHX improves LR in rats after PH by inhibiting hepatocyte apoptosis via the JNK signaling pathway.
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Semba T, Sammons R, Wang X, Xie X, Dalby KN, Ueno NT. JNK Signaling in Stem Cell Self-Renewal and Differentiation. Int J Mol Sci 2020; 21:E2613. [PMID: 32283767 PMCID: PMC7177258 DOI: 10.3390/ijms21072613] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 04/07/2020] [Accepted: 04/07/2020] [Indexed: 12/13/2022] Open
Abstract
C-JUN N-terminal kinases (JNKs), which belong to the mitogen-activated protein kinase (MAPK) family, are evolutionarily conserved kinases that mediate cell responses to various types of extracellular stress insults. They regulate physiological processes such as embryonic development and tissue regeneration, playing roles in cell proliferation and programmed cell death. JNK signaling is also involved in tumorigenesis and progression of several types of malignancies. Recent studies have shown that JNK signaling has crucial roles in regulating the traits of cancer stem cells (CSCs). Here we describe the functions of the JNK signaling pathway in self-renewal and differentiation, which are essential features of various types of stem cells, such as embryonic, induced pluripotent, and adult tissue-specific stem cells. We also review current knowledge of JNK signaling in CSCs and discuss its role in maintaining the CSC phenotype. A better understanding of JNK signaling as an essential regulator of stemness may provide a basis for the development of regenerative medicine and new therapeutic strategies against malignant tumors.
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Affiliation(s)
- Takashi Semba
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (T.S.); (X.W.); (X.X.)
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rachel Sammons
- Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; (R.S.); (K.N.D.)
| | - Xiaoping Wang
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (T.S.); (X.W.); (X.X.)
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xuemei Xie
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (T.S.); (X.W.); (X.X.)
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kevin N. Dalby
- Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; (R.S.); (K.N.D.)
- Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
| | - Naoto T. Ueno
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (T.S.); (X.W.); (X.X.)
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Shohayeb B, Mitchell N, Millard SS, Quinn LM, Ng DCH. Elevated levels of Drosophila Wdr62 promote glial cell growth and proliferation through AURKA signalling to AKT and MYC. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118713. [PMID: 32246948 DOI: 10.1016/j.bbamcr.2020.118713] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 03/09/2020] [Accepted: 03/30/2020] [Indexed: 12/12/2022]
Abstract
WD40-Repeat Protein 62 (WDR62) is required to maintain neural and glial cell populations during embryonic brain growth. Although elevated expression of WDR62 is frequently associated with several tumour types, potential effects of excess WDR62 on proliferative growth remain undefined. Here, we demonstrate that glia specific overexpression of WDR62 in Drosophila larval brains resulted in increased cell size, over-proliferation and increased brain volume, without overt disruption of tissue organization. We further demonstrate WDR62 promoted over-proliferation and brain overgrowth by activating AURKA and pAKT signalling to increase MYC function in glial cells. Together these data suggest WDR62 normally functions in the glial lineage to activate oncogenic signalling networks, promoting proliferation and brain overgrowth.
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Affiliation(s)
- Belal Shohayeb
- School of Biomedical Science, Faculty of Medicine, University of Queensland, St Lucia, Queensland 4067, Australia
| | - Naomi Mitchell
- ACRF Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 260, Australia
| | - S Sean Millard
- School of Biomedical Science, Faculty of Medicine, University of Queensland, St Lucia, Queensland 4067, Australia
| | - Leonie M Quinn
- ACRF Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 260, Australia
| | - Dominic C H Ng
- School of Biomedical Science, Faculty of Medicine, University of Queensland, St Lucia, Queensland 4067, Australia.
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Yang JD, Ahmed F, Mara KC, Addissie BD, Allen AM, Gores GJ, Roberts LR. Diabetes Is Associated With Increased Risk of Hepatocellular Carcinoma in Patients With Cirrhosis From Nonalcoholic Fatty Liver Disease. Hepatology 2020; 71:907-916. [PMID: 31309602 PMCID: PMC6960360 DOI: 10.1002/hep.30858] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 07/16/2019] [Indexed: 12/13/2022]
Abstract
Diabetes increases the risk of liver disease progression and cirrhosis development in patients with nonalcoholic steatohepatitis (NASH). The association between diabetes and the risk of hepatocellular carcinoma (HCC) in NASH patients with cirrhosis is not well quantified. All patients with the diagnosis of NASH cirrhosis seen at Mayo Clinic Rochester between January 2006 and December 2015 were identified. All adult liver transplant registrants with NASH between 2004 and 2017 were identified using the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation registry for external validation. Cox proportional hazard analysis was performed to investigate the association between diabetes and HCC risk. Among 354 Mayo Clinic patients with NASH cirrhosis, 253 (71%) had diabetes and 145 (41%) were male. Mean age at cirrhosis evaluation was 62. During a median follow-up of 47 months, 30 patients developed HCC. Diabetes was associated with an increased risk of developing HCC in univariate (hazard ratio [HR] = 3.6; 95% confidence interval [CI] = 1.1-11.9; P = 0.04) and multivariable analysis (HR = 4.2; 95% CI = 1.2-14.2; P = 0.02). In addition, age (per decade, HR = 1.8; 95% CI = 1.2-2.6; P < 0.01) and low serum albumin (HR = 2.1; 95% CI = 1.5-2.9; P < 0.01) were significantly associated with an increased risk of developing HCC in multivariable analysis. Other metabolic risk factors, including body mass index, hyperlipidemia, and hypertension, were not associated with HCC risk. Among UNOS NASH registrants (N = 6,630), 58% had diabetes. Diabetes was associated with an increased risk of developing HCC in univariate (HR = 1.4; 95% CI = 1.1-1.8; P < 0.01) and multivariable (HR = 1.3; 95% CI = 1.0-1.7; P = 0.03) analysis. Conclusion: Diabetes is associated with an increased risk of HCC in patients with NASH cirrhosis.
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Affiliation(s)
- Ju Dong Yang
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN,Division of Digestive and Liver Diseases, Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, CA,Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, CA,Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA
| | - Fowsiyo Ahmed
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Kristin C. Mara
- Department of Health Science Research, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Benyam D. Addissie
- Division of Gastroenterology and Hepatology, Geisinger Medical Center, Danville, PA
| | - Alina M. Allen
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
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MUC1 oncoprotein mitigates ER stress via CDA-mediated reprogramming of pyrimidine metabolism. Oncogene 2020; 39:3381-3395. [PMID: 32103170 PMCID: PMC7165067 DOI: 10.1038/s41388-020-1225-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 02/12/2020] [Accepted: 02/14/2020] [Indexed: 12/12/2022]
Abstract
The Mucin 1 (MUC1) protein is overexpressed in various cancers and mediates chemotherapy resistance. However, the mechanism is not fully understood. Given that most chemotherapeutic drugs disrupt ER homeostasis as part of their toxicity, and MUC1 expression is regulated by proteins involved in ER homeostasis, we investigated the link between MUC1 and ER homeostasis. MUC1 knockdown in pancreatic cancer cells enhanced unfolded protein response (UPR) signaling and cell death upon ER stress induction. Transcriptomic analysis revealed alterations in the pyrimidine metabolic pathway and cytidine deaminase (CDA). ChIP and CDA activity assays showed that MUC1 occupied CDA gene promoter upon ER stress induction correlating with increased CDA expression and activity in MUC1-expressing cells as compared to MUC1 knockdown cells. Inhibition of either the CDA or pyrimidine metabolic pathway diminished survival in MUC1-expressing cancer cells upon ER stress induction. Metabolomic analysis demonstrated that MUC1-mediated CDA activity corresponded to deoxycytidine to deoxyuridine metabolic reprogramming upon ER stress induction. The resulting increase in deoxyuridine mitigated ER stress-induced cytotoxicity. Additionally, given 1) the established roles of MUC1 in protecting cells against reactive oxygen species (ROS) insults, 2) ER stress-generated ROS further promote ER stress and 3) the emerging anti-oxidant property of deoxyuridine, we further investigated if MUC1 regulated ER stress by a deoxyuridine-mediated modulation of ROS levels. We observed that deoxyuridine could abrogate ROS-induced ER stress to promote cancer cell survival. Taken together, our findings demonstrate a novel MUC1-CDA axis of the adaptive UPR that provides survival advantage upon ER stress induction.
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Dimri M, Satyanarayana A. Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12020491. [PMID: 32093152 PMCID: PMC7072513 DOI: 10.3390/cancers12020491] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/β-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment. In this review, we elaborated on our current understanding of the signaling pathways involved in the development and initiation of HCC and anticipate the potential targets for therapeutic drug development.
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50
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Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity. Int J Mol Sci 2020; 21:ijms21031102. [PMID: 32046099 PMCID: PMC7037308 DOI: 10.3390/ijms21031102] [Citation(s) in RCA: 480] [Impact Index Per Article: 96.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/04/2020] [Accepted: 02/05/2020] [Indexed: 12/12/2022] Open
Abstract
Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.
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