Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells

BMC Cancer

Ann H Rosendahl¹  Roland Andersson¹  Katarzyna Said¹  Emelie Karnevi¹ 

[1]Department of Surgery, Clinical Sciences Lund, Skåne University Hospital and Lund University, Lund SE-221 84, Sweden

关键词: Signalling;    Insulin-like growth factor (IGF);    Metformin;    Hyperglycaemia;    Type 2 diabetes mellitus;    Pancreatic cancer;   

Others  :  1079756
DOI  :  10.1186/1471-2407-13-235

 received in 2012-10-09, accepted in 2013-04-30,  发布年份 2013

【 摘 要 】

Background

Epidemiological studies have shown direct associations between type 2 diabetes and obesity, both conditions associated with hyperglycaemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin. In this study, the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin were investigated.

Methods

The human pancreatic cancer cell lines AsPC-1, BxPC-3, PANC-1 and MIAPaCa-2 were grown in normal (5 mM) or high (25 mM) glucose conditions, with or without metformin. The influence by metformin on proliferation, apoptosis and the AMPK and IGF-IR signalling pathways were evaluated in vitro.

Results

Metformin significantly reduced the proliferation of pancreatic cancer cells under normal glucose conditions. Hyperglycaemia however, protected against the metformin-induced growth inhibition. The anti-proliferative actions of metformin were associated with an activation of AMP-activated protein kinase AMPK^Thr172 together with an inhibition of the insulin/insulin-like growth factor-I (IGF-I) receptor activation and downstream signalling mediators IRS-1 and phosphorylated Akt. Furthermore, exposure to metformin during normal glucose conditions led to increased apoptosis as measured by poly(ADP-ribose) polymerase (PARP) cleavage. In contrast, exposure to high glucose levels promoted a more robust IGF-I response and Akt activation which correlated to stimulated AMPK^Ser485 phosphorylation and impaired AMPK^Thr172 phosphorylation, resulting in reduced anti-proliferative and apoptotic effects by metformin.

Conclusion

Our results indicate that metformin has direct anti-tumour activities in pancreatic cancer cells involving AMPK^Thr172 activation and suppression of the insulin/IGF signalling pathways. However, hyperglycaemic conditions enhance the insulin/IGF-I responses resulting in an altered AMPK activation profile and prevent metformin from fully switching off the growth promoting signals in pancreatic cancer cells.

【 授权许可】

   
2013 Karnevi et al.; licensee BioMed Central Ltd.

【 图 表 】

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