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Abstract
Background/aim: Metformin is an antidiabetic drug that has been reported to have antitumor activity in many cancer types. This study investigated the molecular mechanisms underlying the antitumor effect of metformin.

Materials and methods: We investigated the molecular mechanism of the antitumor effect of metformin alone and in combination with AKT serine/threonine kinase (AKT) inhibition via cell viability and western blot analyses.

Results: Notably, metformin increased the phosphorylation of AKT at serine 473 using protein array screening. Metformin-induced AKT activation was markedly suppressed by siRNA targeting activating transcription factor 4 (ATF4) but not AMP-activated protein kinase α. These results indicate that AKT activation by metformin was induced in an ATF4-dependent and AMPKα-independent manner. Treatment using metformin combined with MK-2206, an AKT inhibitor, or a siRNA for AKT markedly reduced the viability of cells compared with those cells treated with these agents alone. In addition, MK-2206 increased cell sensitivity to the combination of metformin with ionizing radiation or cisplatin.

Conclusion: Inhibition of AKT can enhance the antitumor effect of metformin and would be a promising strategy to sensitize non-small-cell lung cancer to a combination of metformin with radiation or cisplatin.

Affiliations

Se-Kyeong Jang  1   2 , Sung-Eun Hong  3 , DA-Hee Lee  1 , Ji Yea Kim  1 , Ji-Young Kim  3 , Jungil Hong  2 , In-Chul Park  4 , Hyeon-Ok Jin  5
1 Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
2 Department of Food and Microbial Technology, Seoul Women's University, Seoul, Republic of Korea.
3 KIRAMS Radiation Biobank, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
4 Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea; parkic@kirams.re.kr hyeonok@kirams.re.kr.
5 KIRAMS Radiation Biobank, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea parkic@kirams.re.kr hyeonok@kirams.re.kr.