Targeting Dynamin-Related Protein 1 and Glucose Metabolism Reverses Acquired Resistance to Sorafenib in Liver Cancer

Drug resistance limits the therapeutic effects of multi-kinase inhibitor, sorafenib, for patients with advanced stage liver cancer. Aberrant mitochondrial dynamics and metabolism are now considered hallmarks of liver tumors. Thus, the present study was to clarify the relationship between mitochondrial dynamics and metabolism, and explore the combination of targeting therapies for sorafenib-resistant liver cancer. Mitochondrial metabolism switch was evaluated by oxygen consumption ratio, glucose uptake and lactate production. Cell counting, colony formation, cell cycle assays, time-lapse cell motility and Transwell assays were used to evaluate cell growth, migration and invasion capacities. Orthotopic xenograft models were used to illustrate the therapeutic effects of the combined administration of the oxidative phosphorylation (OXPHOS) inhibitor, IACS-010759, with the Drp1 inhibitor, mdivi-1. In the present study, Drp1-mediated mitochondrial fission and the hyper-glycolytic phenotype were dominant in sorafenib-resistant liver cancer cells, which were closely correlated with tumor prognosis. Drp1 knockdown or inhibition impaired the invasive and metastatic capacities of cancer cells, but promoted cell cycle and cellular growth, which was due to the metabolic shift from aerobic glycolysis to OXPHOS. Additional administration of the OXPHOS inhibitor, IACS-010759, combined with the Drp1 inhibitor, mdivi-1, alleviated the tumor progression of sorafenib-resistant liver cancer markedly, both in terms of proliferation and metastasis. The findings of the current study indicated that mitochondrial dynamics had an impact on mitochondrial metabolism in sorafenib-resistant liver cancer cells. Consequently, the combined targeting of mitochondrial dynamics and metabolism might be an effective way to overcome sorafenib resistance in liver cancer.