biostudies-literatureJin PBasic and Applied Basic Research Foundation of Guangdong Provincee16082https://www.ebi.ac.uk/biostudies/studies/S-EPMC9728056biostudies-literatureUnknown14(12)Metformin, a well-known antidiabetic drug, has been repurposed for cancer treatment; however, recently observed drug resistance and tumor metastasis have questioned its further application. Here, we found that long-term metformin exposure led to metabolic adaptation of hepatocellular carcinoma (HCC) cells, which was characterized by an obvious epithelial-mesenchymal transition (EMT) phenotype and compensatory elevation of oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mitochondrial membrane, was upregulated to promote tumor metastasis in response to metformin-induced metabolic stress. Mechanistically, TOMM34 interacted with ATP5B to preserve F₁ F_O -ATPase activity, which conferred mitochondrial OXPHOS and ATP production. This metabolic preferenEMBO molecular medicineDisrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis.PMC97280562019B030302012Jiang JZhou LHuang CChen HNDing NXie NLi LWei YQin SZhang WZhang THuang ZZhang ZNice ECLuo MGao WJin PLi BPeng LMing HfalseDisrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis.Metformin, a well-known antidiabetic drug, has been repurposed for cancer treatment; however, recently observed drug resistance and tumor metastasis have questioned its further application. Here, we found that long-term metformin exposure led to metabolic adaptation of hepatocellular carcinoma (HCC) cells, which was characterized by an obvious epithelial-mesenchymal transition (EMT) phenotype and compensatory elevation of oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mitochondrial membrane, was upregulated to promote tumor metastasis in response to metformin-induced metabolic stress. Mechanistically, TOMM34 interacted with ATP5B to preserve F₁ F_O -ATPase activity, which conferred mitochondrial OXPHOS and ATP production. This metabolic preferen2022-01-01T00:00:00Z2022 Dec2026-05-27T23:40:26.133Z2024-11-13T21:51:13.773ZS-EPMC97280563632155510.15252/emmm.202216082