Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP–PKA–EGFR–STAT3 axis

Oncogene volume 36, pages 4135–4149 (2017)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

References

  1. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 2011; 378: 31–40.

    Article  CAS  PubMed  Google Scholar 

  2. El-Serag HB, Hampel H, Javadi F . The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006; 4: 369–380.

    Article  PubMed  Google Scholar 

  3. Farrell GC, Wong VW, Chitturi S . NAFLD in Asia–as common and important as in the West. Nat Rev Gastroenterol Hepatol 2013; 10: 307–318.

    Article  CAS  PubMed  Google Scholar 

  4. Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007; 30: 1212–1218.

    Article  PubMed  Google Scholar 

  5. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A . Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87–108.

    Article  PubMed  Google Scholar 

  6. Wang P, Kang D, Cao W, Wang Y, Liu Z . Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev 2012; 28: 109–122.

    Article  PubMed  Google Scholar 

  7. Hosokawa T, Kurosaki M, Tsuchiya K, Matsuda S, Muraoka M, Suzuki Y et al. Hyperglycemia is a significant prognostic factor of hepatocellular carcinoma after curative therapy. World J Gastroenterol 2013; 19: 249–257.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Drucker DJ . The biology of incretin hormones. Cell Metab 2006; 3: 153–165.

    Article  CAS  PubMed  Google Scholar 

  9. Xu G, Stoffers DA, Habener JF, Bonner-Weir S . Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999; 48: 2270–2276.

    Article  CAS  PubMed  Google Scholar 

  10. Nauck M . Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2016; 18: 203–216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S, Candelaresi C et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 2011; 31: 1285–1297.

    Article  CAS  PubMed  Google Scholar 

  12. Ding X, Saxena NK, Lin S, Gupta NA, Anania FA . Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 2006; 43: 173–181.

    Article  CAS  PubMed  Google Scholar 

  13. Nauck MA, Friedrich N . Do GLP-1-based therapies increase cancer risk? Diabetes Care 2013; 36: S245–S252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fan R, Li X, Gu X, Chan JC, Xu G . Exendin-4 protects pancreatic beta cells from human islet amyloid polypeptide-induced cell damage: potential involvement of AKT and mitochondria biogenesis. Diabetes Obes Metab 2010; 12: 815–824.

    Article  CAS  PubMed  Google Scholar 

  15. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC . Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011; 141: 150–156.

    Article  CAS  PubMed  Google Scholar 

  16. Feng X, Dong K, Chaing W, Bhutada NS, Inciardi J, Woldemariam T et al. Assessing pancreatic cancer risk associated with dipeptidyl peptidase 4 inhibitors: data mining of FDA adverse event reporting system (FAERS). J Pharmacovigilance 2013; 1: 110.

    Google Scholar 

  17. Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T et al. Pancreatic safety of incretin-based drugs–FDA and EMA assessment. N Engl J Med 2014; 370: 794–797.

    Article  CAS  PubMed  Google Scholar 

  18. Koehler JA, Drucker DJ . Activation of glucagon-like peptide-1 receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells. Diabetes 2006; 55: 1369–1379.

    Article  CAS  PubMed  Google Scholar 

  19. Koehler JA, Kain T, Drucker DJ . Glucagon-like peptide-1 receptor activation inhibits growth and augments apoptosis in murine CT26 colon cancer cells. Endocrinology 2011; 152: 3362–3372.

    Article  CAS  PubMed  Google Scholar 

  20. Ligumsky H, Wolf I, Israeli S, Haimsohn M, Ferber S, Karasik A et al. The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res Treat 2012; 132: 449–461.

    Article  CAS  PubMed  Google Scholar 

  21. Nomiyama T, Kawanami T, Irie S, Hamaguchi Y, Terawaki Y, Murase K et al. Exendin-4, a GLP-1 receptor agonist, attenuates prostate cancer growth. Diabetes 2014; 63: 3891–3905.

    Article  CAS  PubMed  Google Scholar 

  22. Kohli R, Kirby M, Xanthakos SA, Softic S, Feldstein AE, Saxena V et al. High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis. Hepatology 2010; 52: 934–944.

    Article  CAS  PubMed  Google Scholar 

  23. Lee JS, Chu IS, Mikaelyan A, Calvisi DF, Heo J, Reddy JK et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 2004; 36: 1306–1311.

    Article  CAS  PubMed  Google Scholar 

  24. Delghandi MP, Johannessen M, Moens U . The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells. Cell Signal 2005; 17: 1343–1351.

    Article  CAS  PubMed  Google Scholar 

  25. Barbier AJ, Poppleton HM, Yigzaw Y, Mullenix JB, Wiepz GJ, Bertics PJ et al. Transmodulation of epidermal growth factor receptor function by cyclic AMP-dependent protein kinase. J Biol Chem 1999; 274: 14067–14073.

    Article  CAS  PubMed  Google Scholar 

  26. Absood A, Hu B, Bassily N, Colletti L . VIP inhibits human HepG2 cell proliferation in vitro. Regul Pept 2008; 146: 285–292.

    Article  CAS  PubMed  Google Scholar 

  27. Hsuan JJ . Oncogene regulation by growth factors. Anticancer Res 1993; 13: 2521–2532.

    CAS  PubMed  Google Scholar 

  28. Shao H, Cheng HY, Cook RG, Tweardy DJ . Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res 2003; 63: 3923–3930.

    CAS  PubMed  Google Scholar 

  29. Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS . Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol 1997; 8: 1197–1206.

    Article  CAS  PubMed  Google Scholar 

  30. Carpenter RL, Lo HW . STAT3 target genes relevant to human cancers. Cancers (Basel) 2014; 6: 897–925.

    Article  CAS  Google Scholar 

  31. Chen HP, Shieh JJ, Chang CC, Chen TT, Lin JT, Wu MS et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 2013; 62: 606–615.

    Article  CAS  PubMed  Google Scholar 

  32. Chang CH, Lin JW, Wu LC, Lai MS, Chuang LM, Chan KA . Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus. Hepatology 2012; 55: 1462–1472.

    Article  CAS  PubMed  Google Scholar 

  33. Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 2010; 51: 1584–1592.

    Article  CAS  PubMed  Google Scholar 

  34. Korner M, Stockli M, Waser B, Reubi JC . GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 2007; 48: 736–743.

    Article  CAS  PubMed  Google Scholar 

  35. Kovach SJ, Price JA, Shaw CM, Theodorakis NG, McKillop IH . Role of cyclic-AMP responsive element binding (CREB) proteins in cell proliferation in a rat model of hepatocellular carcinoma. J Cell Physiol 2006; 206: 411–419.

    Article  CAS  PubMed  Google Scholar 

  36. Otsuka M, Kato N, Shao RX, Hoshida Y, Ijichi H, Koike Y et al. Vitamin K2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation. Hepatology 2004; 40: 243–251.

    Article  CAS  PubMed  Google Scholar 

  37. Mayoral R, Fernandez-Martinez A, Bosca L, Martin-Sanz P . Prostaglandin E2 promotes migration and adhesion in hepatocellular carcinoma cells. Carcinogenesis 2005; 26: 753–761.

    Article  CAS  PubMed  Google Scholar 

  38. Caretta A, Mucignat-Caretta C . Protein kinase A in cancer. Cancers (Basel) 2011; 3: 913–926.

    Article  CAS  Google Scholar 

  39. Ito Y, Takeda T, Sakon M, Tsujimoto M, Higashiyama S, Noda K et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer 2001; 84: 1377–1383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hopfner M, Sutter AP, Huether A, Schuppan D, Zeitz M, Scherubl H . Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma. J Hepatol 2004; 41: 1008–1016.

    Article  PubMed  Google Scholar 

  41. Schiffer E, Housset C, Cacheux W, Wendum D, Desbois-Mouthon C, Rey C et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 2005; 41: 307–314.

    Article  CAS  PubMed  Google Scholar 

  42. Ito Y, Matsuura N, Sakon M, Miyoshi E, Noda K, Takeda T et al. Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence. Hepatology 1999; 30: 90–99.

    Article  CAS  PubMed  Google Scholar 

  43. Watanabe J, Kushihata F, Honda K, Sugita A, Tateishi N, Mominoki K et al. Prognostic significance of Bcl-xL in human hepatocellular carcinoma. Surgery 2004; 135: 604–612.

    Article  PubMed  Google Scholar 

  44. Yang Y, Zhu J, Gou H, Cao D, Jiang M, Hou M . Clinical significance of Cox-2, Survivin and Bcl-2 expression in hepatocellular carcinoma (HCC). Med Oncol 2011; 28: 796–803.

    Article  CAS  PubMed  Google Scholar 

  45. Boehm AL, Sen M, Seethala R, Gooding WE, Freilino M, Wong SM et al. Combined targeting of epidermal growth factor receptor, signal transducer and activator of transcription-3, and Bcl-X(L) enhances antitumor effects in squamous cell carcinoma of the head and neck. Mol Pharmacol 2008; 73: 1632–1642.

    Article  CAS  PubMed  Google Scholar 

  46. Kang ZF, Deng Y, Zhou Y, Fan RR, Chan JC, Laybutt DR et al. Pharmacological reduction of NEFA restores the efficacy of incretin-based therapies through GLP-1 receptor signalling in the beta cell in mouse models of diabetes. Diabetologia 2013; 56: 423–433.

    Article  CAS  PubMed  Google Scholar 

  47. Yu Z, Gao YQ, Feng H, Lee YY, Li MS, Tian Y et al. Cell cycle-related kinase mediates viral-host signalling to promote hepatitis B virus-associated hepatocarcinogenesis. Gut 2014; 63: 1793–1804.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study is supported by the Collaborative Research Fund (C4017-14G) and the General Research Fund (14120816) of the Research Grants Council of Hong Kong, National Natural Science Foundation of China (81272305, 81170722, 81270438, 81302167 and 81501210) and Focused Investments Scheme B (1907301) of the Chinese University of Hong Kong.

Author information

Authors and Affiliations

  1. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China

    M Zhou & H Sun

  2. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China

    M T S Mok, Y Huang & A S L Cheng

  3. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China

    M T S Mok & A S L Cheng

  4. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China,

    H Sun

  5. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China

    A W Chan

  6. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China

    A S L Cheng

  7. Diabetes Center and Department of Endocrinology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China,

    G Xu

Authors
  1. M Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M T S Mok
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A W Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A S L Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to A S L Cheng or G Xu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, M., Mok, M., Sun, H. et al. The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP–PKA–EGFR–STAT3 axis. Oncogene 36, 4135–4149 (2017). https://doi.org/10.1038/onc.2017.38

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.38

This article is cited by

Search

Advanced search

Quick links