The anticancer effect of metformin targets VDAC1 via ER-mitochondria interactions-mediated autophagy in HCC

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. Metformin, a common type 2 diabetes drug, is known for its glucose-lowering effects. The study used several cell lines and advanced techniques to investigate how Metformin induces cancer cell death. This experimental research included cell cultures and molecular analysis. They found that Metformin targets a mitochondrial protein called VDAC1. This interaction disrupts energy production and increases autophagy, leading to cancer cell death. The results showed that Metformin binds to VDAC1, reducing mitochondrial calcium and ATP levels, which activates autophagy and kills cancer cells. The researchers concluded that the ionic interaction of Metformin with VDAC1 is critical for its anticancer effects. Future studies could explore Metformin as a treatment for cancers with high VDAC1 expression. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.