2022.11.02 Jin Ping's research results were published in the authoritative academic journal EMBO molecular medicine

On November 2, 2022, our student Jin Ping published a research paper entitled "Disrupting metforminadaptation of liver cancer cells by targeting the TOMM34/ATP5B axis" in the international authoritative academic journal EMBO Molecular medicine, revealing the molecular mechanism by which the mitochondrial outer membrane protein TOMM34 mediates the adaptation of liver cancer to metformin by maintaining oxidative phosphorylation of cells. Jin Ping is the first author of the paper, and the co-first author is Dr. Jiang Jingwen, and our supervisor Professor Huang Canhua is the corresponding author of the article. In addition, the work was also supported by Academician Wei Yuquan, Director of the State Key Laboratory of Biotherapy of Sichuan University, Professor Zhang Wei of the Mental Health Center of West China Hospital of Sichuan University, and Edouard C. Professor Nice and Associate Professor Chen Haining of the Department of Gastrointestinal Surgery of West China Hospital of Sichuan University.

In recent years, metformin, a hypoglycemic drug mainly used to treat diabetes, has been shown to have excellent anti-tumor potential in a variety of cancers, including liver cancer; however, long-term use of metformin has also inevitably led to the problem of tumor resistance. Studies have shown that some metformin-tolerant tumor cells exhibit a significant epithelial-mesenchymal transition (EMT) phenotype, accompanied by continuous activation of the Akt/Snail1 signaling pathway. Previous studies found that tumor cells adapted to metformin treatment exhibited up-regulation of transcription of oxidative phosphorylation (OXPHOS) -related genes, and the proliferation index of such tumor cells was correspondingly high, suggesting that the up-regulation of oxidative phosphorylation may be related to the tolerance of tumor cells to metformin. Therefore, exploring specific molecular mechanisms involved in these metabolic adaptation processes may help to improve the sensitivity of tumor cells to metformin, and thus explore a combination therapy strategy for better therapeutic effect.

We first used the PDX model to verify the existence of metformin metabolic adaptation in liver cancer cells. Mass spectrometry analysis, mitochondrial protein database, and biochemical experiments showed that the mitochondrial outer membrane protein TOMM34 played an important role in promoting metformin adaptation and metastasis in liver cancer cells. Subsequently, transcriptome sequencing, mass spectrometry, and various molecular cytology experiments proved that TOMM34, by binding to ATP5B, ensured the activity of mitochondrial complexes and the level of oxidative phosphorylation in cells, and promoted the survival of tumor cells under metformin treatment. In order to explore the possibility of targeting the TOMM34-ATP5B signaling axis to benefit the treatment of liver cancer, we screened for the oxidative phosphorylation inhibitor Gboxin and found that it could inhibit the ATP level in liver cancer cells and the metastatic ability of liver cancer cells. This inhibition was achieved by disrupting the interaction between TOMM34 and ATP5B. Further in vivo and in vitro experimental results showed that Gboxin can also inhibit the metastatic ability of metformin-adapted hepatocellular carcinoma cells, and the combination with metformin can exert a better inhibitory effect on hepatocellular carcinoma. These findings reveal the molecular mechanism of TOMM34-ATP5B signaling axis mediating metformin adaptation in hepatocellular carcinoma cells, providing a potential combination regimen for clinical metformin use.