Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis

Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis

Abstract 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 carcin...

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Detalhes bibliográficos
Principais autores: Ping Jin, Jingwen Jiang, Li Zhou, Zhao Huang, Siyuan Qin, Hai‐Ning Chen, Liyuan Peng, Zhe Zhang, Bowen Li, Maochao Luo, Tingting Zhang, Hui Ming, Ning Ding, Lei Li, Na Xie, Wei Gao, Wei Zhang, Edouard C Nice, Yuquan Wei, Canhua Huang
Formato: Artigo
Idioma:English
Publicado em: Springer Nature 2022-11-01
coleção:EMBO Molecular Medicine
Assuntos:
hepatocellular carcinoma
metastasis
metformin adaptation
oxidative phosphorylation
TOMM34
Acesso em linha:https://doi.org/10.15252/emmm.202216082
Descrição
Resumo:Abstract 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 F1FO‐ATPase activity, which conferred mitochondrial OXPHOS and ATP production. This metabolic preference for OXPHOS suggested a large requirement of energy supply by cancer cells to survive and spread in response to therapeutic stress. Notably, disturbing the interaction between TOMM34 and ATP5B using Gboxin, a specific OXPHOS inhibitor, increased sensitivity to metformin and suppressed tumor progression both in vitro and in vivo. Overall, this study demonstrates a molecular link of the TOMM34/ATP5B‐ATP synthesis axis during metformin adaptation and provides promising therapeutic targets for metformin sensitization in cancer treatment.
ISSN:1757-4676
1757-4684

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