Abstract
Abstract The dynamic nature of tumor microenvironments contributes to tumor heterogeneity generating subpopulations of cells that are resistant to treatment in glioblastoma (GBM). The high recurrent rate of GBM tumors in patients can partially be explained by the presence of glioma stem cells (GSCs), which are thought to give rise to resistant clones against chemotherapy. As solid tumors expand, cancer cells can disrupt the tumor microenviroment by disrupting the blood brain barrier. Pericytes and astrocytes detach from the vascular endothelial cells, forming leaky vessels, which leads to thrombosis and eventually necrosis. Necrosis is a hallmark signature of GBM, as oxygen and nutrient supply runs low which can be observed through contrast imaging. Cancer cells go through a phenotypic change by upregulating stemness genes and glycolytic metabolism. Cells migrate away from hypoxic and nutrient deprived regions forming pseudopalisading cells which are an indication of cells becoming more invasive and malignant. Mitochondrial protein trafficking is a tightly regulated mechanism which selectively allows specific peptides carrying a mitochondrial targeting sequence (MTS) to be transported through the TOM40 and TIM23 complexes. Magmas, a TIM23 subunit, negatively regulates DNAJC19 by inhibiting its stimulatory activity on Hsp70 in the mitochondrial matrix. The regulation of the ATPase activity on Hsp70 is critical for processing pre-cursor proteins through the TIM23 complex into the mitochondrial matrix. Our laboratory has uncovered a novel role of Magmas activity in GBM cells under serum starved conditions in vitro. Magmas is downregulated in serum starved cells which allows for an increase of mitochondrial matrix proteins, which include key subunits important for forming electron transport chain complexes. This influx of ETC proteins can explain how cells are able to reduce aerobic glycolysis and increase oxidative phosphorylation (OXPHOS), a mechanism that can be exploited for potential therapeutic treatment in patients with GBM.
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