The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP-PKA-EGFR-STAT3 axis.
Epidemiological studies have demonstrated a close association of type 2 diabetes and hepatocellular carcinoma (HCC). Exenatide (Ex-4), a potent diabetes drug targeting glucagon-like peptide-1 receptor (GLP-1R), is protective against non-alcoholic fatty liver disease (NAFLD). However, the Ex-4 function and GLP-1R status have yet been explored in HCC. Herein we investigated the effect of Ex-4 in diethylnitrosamine (DEN)-treated mice consuming control or high-fat high-carbohydrate diet. Administration of Ex-4 significantly improved obesity-induced hyperglycemia and hyperlipidemia and reduced HCC multiplicity in obese DEN-treated mice, in which suppressed proliferation and induced apoptosis were confined to tumor cells. The tumor suppression effects of Ex-4 were associated with high expression of GLP-1R and activation of cyclic AMP (cAMP) and protein kinase A (PKA). Importantly, Ex-4 also downregulated epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3), which lie downstream of cAMP-PKA signaling, resulting in suppression of multiple STAT3-targeted genes including c-Myc, cyclin D1, survivin, Bcl-2 and Bcl-xl. The growth inhibitory effects of Ex-4 were consistent in GLP-1R-abundant hepatoma cell lines and xenograft mouse model, wherein both PKA and EGFR had obligatory roles in mediating Ex-4 functions. In addition, Ex-4 also effectively suppressed inflammatory and fibrotic phenotypes in mice fed with methionine-choline-deficient (MCD) diet and choline-deficient ethionine-supplemented (CDE) diet, respectively. In summary, Ex-4 elicits protective functions against NAFLD and obesity-associated HCC through cAMP-PKA-EGFR-STAT3 signaling, suggesting its administration as a novel approach to reduce HCC risk in diabetic patients.
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
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Zhou
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
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Mok
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.|Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Sun
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
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Chan
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
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Huang
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.|State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
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Cheng
Diabetes Center and Department of Endocrinology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
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Xu
D000818:Animals; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000077270:Exenatide; D006801:Humans; D006943:Hyperglycemia; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010455:Peptides / Q000494:pharmacology*; D012307:Risk Factors; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014688:Venoms / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
D010455:Peptides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014688:Venoms; D000077270:Exenatide; D000242:Cyclic AMP; C512478:EGFR protein, human; D066246:ErbB Receptors; D000097789:Glucagon-Like Peptide-1 Receptor Agonists