The Regulatory Roles of Mitochondrial Metabolism Dynamics and Mitochondria Calcium Uniporter (MCU) in Bevacizumab Resistance of GBM

Adapted oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle activations are essential tumor microenvironments for abnormal energy consumption to acquire malignancy and drug resistance during cancer development and progression. To elucidate the molecular mechanism related to the mitochondrial metabolic dynamics and drug resistance in glioblastoma (GBM), a longitudinal GBM orthotopic mouse model with acquired resistance to bevacizumab is established. The longitudinal proteomic analysis results show that OXPHOS, TCA, and calcium signaling gene sets are enriched in the bevacizumab pre-resistance phase for preparing resistance phase. Then, the APEX system to GBM to biotinylate and purify proteins of the mitochondria matrix is applied. The organelle specific proteomic analysis shows that the pore-forming subunits of the mitochondrial calcium uniporter protein (MCU) are essential for acquiring bevacizumab resistance. Additionally, a combination effect of hypoxia and the MCU-specific inhibitor DS16570511 in vitro shows that cell growth and proliferation are reduced via inhibition of NF-kappa B and CEBP/beta signaling pathways. In conclusion, the hypoxic tumor microenvironment induced by bevacizumab treatment affects mitochondrial metabolic dynamics, and targeting MCU is a promising therapeutic option in combination with bevacizumab in recurrent GBM.