Abstract 65: Metformin inhibits in vivo growth of MC38 colon carcinoma in the absence of LKB1 expression

Abstract There is evidence that metformin has anti-neoplastic activity in diabetic cancer patients. In hepatocytes, metformin administration leads to the LKB1-dependent activation of AMPK and inhibition of gluconeogenesis which can lower insulin levels. In neoplastic cells in vitro, metformin-induced activation of AMPK leads to inhibition of both protein synthesis and cell proliferation. Our previous results showed that metformin inhibits LLC1 tumor growth in mice on a high energy diet that induced hyperinsulinemia, while having no effect on tumor growth of mice on a control diet, thus raising questions regarding the roles of direct AMPK mediated anti-neoplastic effects of metformin vs indirect anti-neoplastic effects attributable to reduction of insulin levels. We extended this work using MC38 colon carcinoma with shRNA to knockdown LKB1 (LKB1-). As expected, knockdown of LKB1 conferred resistance to the in vitro growth inhibitory actions of metformin. We proceeded with an in vivo study to compare growth of MC38-LKB1- and MC38 control tumors in mice on either a high energy or control diet, with or without metformin. Metformin was administered daily and the experiment was carried out with each mouse bearing a MC38-LKB1- tumor on one flank and a MC38 control tumor on the other. Metformin had no effect on the insulin levels of mice on the control diet, but significantly reduced the insulin levels of mice on the high energy diet. Tumors of mice on the high energy diet were twice the volume of tumors of mice on the control diet, regardless of LKB1 status. Metformin significantly inhibited growth of both MC38-LKB1- and MC38 control tumors in mice on the high energy diet. These observations suggest that despite its direct in vitro growth inhibitory activity involving activation of AMPK, the anti-neoplastic activity of the drug in vivo, in the context of hyperinsulinemia, is attributable to the actions of the drug on the liver. Consistent with this conclusion, we observed that metformin administration reduced insulin receptor activation in both MC38-LKB1- and MC38 control tumors of mice on the high energy diet. In addition, metformin attenuated tumor growth in MC38-LKB1- cells in mice on the control diet, but had no effect on MC38 control cells. Immunoblotting confirmed that unlike MC38 control cells, LKB1- cells did not undergo autophagy in the presence of metformin. We confirmed these results in vitro and found that MC38-LKB1- treated with metformin, in conditions of low glucose, underwent apoptosis whereas LKB1- cells treated with metformin in conditions of high glucose were insensitive to metformin. MC38 control cells were equally sensitive to the growth inhibitory effects of metformin at both high and low glucose conditions. These results suggest that metformin and similar compounds deserve clinical evaluation, but that their activity may be restricted to subsets based on molecular pathology of the tumor and metabolic status of the host. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 65.

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