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Exp. Mol. Med., 03 December 2024 | https://doi.org/10.1038/s12276-024-01357-1 The anticancer effect of metformin targets VDAC1 via ER-mitochondria interactions-mediated autophagy in HCC

Minjeong Ko ^1,5, Jiho Kim ^1,5, Raudah Lazim ^2,5, Ju Yeon Lee ^3,4, Jin Young Kim ^3,4, Vijayakumar Gosu ², Yoonji Lee ², Sun Choi^2,* and Ho Jeong Kwon ^1,*

¹Chemical Genomics Leader Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
²Global AI Drug Discovery Center, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
³Research Center of Bioconvergence Analysis, Korea Basic Science Institute, Ochang, Republic of Korea.
⁴Critical Diseases Diagnostics Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
⁵These authors contributed equally: Minjeong Ko, Jiho Kim, Raudah Lazim.

^*Corresponding authors: correspondence to Sun Choi or Ho Jeong Kwon

Abstract

Metformin (MetF) is used worldwide as a first-line therapy for type 2 diabetes. Recently, interest in the pleiotropic effects of MetF, such as its anticancer and antiaging properties, has increased. However, the molecular target of MetF and the detailed mechanism underlying its ability to inhibit cell growth through autophagy induction remain incompletely understood. In this study, using an innovative label-free drug affinity responsive target stability (DARTS)-LC-MS/MS method, we discovered that mitochondrial voltage-dependent anion channel 1 (VDAC1) is a novel binding protein involved in the induction of autophagy-related cell death by high-dose MetF in hepatocellular carcinoma (HCC). Computational alanine scanning mutagenesis revealed that MetF and VDAC1 (D9, E203) interact electrostatically. MetF disrupts the IP₃R-GRP75-VDAC1 complex, which plays a key role in stabilizing mitochondria-associated ER membranes (MAMs), by binding to VDAC1. This disruption leads to increased cytosolic calcium levels, thereby contributing to autophagy induction. MetF also decreased the AMP/ATP ratio and activated the AMPK pathway. Cells with genetic knockdown of VDAC1 mimicked the activity of MetF. In conclusion, this study provides new insights into the involvement of MetF in ionic interactions with VDAC1, contributing to its anticancer effects in HCC. These findings help elucidate the diverse biological and pharmacological effects of MetF, particularly its influence on autophagy, as well as the potential of MetF as a therapeutic agent for diseases characterized by VDAC1 overexpression.

논문정보

형식Research article
게재일2024년 12월 (BRIC 등록일 2024-12-04)
연구진국내 연구진
분야 의약학 > 약학

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