Metformin (1.1-dimethylbiguanide hydrochloride), a widely used antidiabetic drug, has been reported to display potent anticancer properties in various types of cancers, including neuroendocrine tumors. Recently, a potential synergistic activity between metformin and octreotide (SSA) in Pancreatic Neuroendocrine Tumors (P-NETs) has been proposed. AIP (aryl hydrocarbon receptor-interacting protein) acts as tumor suppressor gene in neuroendocrine tumors at pituitary level and it is up-regulated by SSA. We investigated the effects of metformin on P-NETs cell proliferation, apoptosis and colony formation, the potential synergistic effect between metformin and octreotide and the possible role of AIP pathway in mediating these effects. We found that in QGP-1 cells metformin significantly inhibited cell proliferation (−37±2% P<0.001 vs basal at 10 mM). We showed no additive effect between Metformin and Octreotide on P-NETs cell proliferation. Moreover, metformin incubation reduced colony formation, cells amount after 7 days (−66±6% P<0.001 vs basal) and it promoted apoptosis (+150±8% P<0.05 vs basal). As expected, octreotide induced AIP up-regulation (+60±11% P<0.05 vs basal), and surprisingly, AIP expression levels were also increased by metformin (+90±13% P<0.05 vs basal). In addition, AIP silencing abolished the antiproliferative and proapoptotic effects of metformin, confirming its involvement in mediating metformin effects. Interestingly, metformin decreased HSP70 expression, increased Zac1 and AhR expression levels. These effects were totally abolished in QGP-1 cells lacking AIP. In conclusion, metformin acts as anticancer agent in P-NET cells, its activity is mediated by AIP and its interacting proteins, HSP70, AHR and Zac1. These findings provide a novel insight into the antitumorigenic mechanism of metformin.
20 - 23 May 2017
European Society of Endocrinology