The role of mitochondrial chaperon TRAP1 in tumorigenesis under hypoxia in brain tumor

Abstract

The tumor necrosis factor receptor-associated protein 1 (TRAP1), a molecular chaperone heat shock protein 90 (Hsp90) family protein in mitochondria, has been reported to regulates metabolic homeostasis. TRAP1 is over-expressed in various cancer cells. It protects their client proteins to escape from cell death, regulates activity of the electron transport chain, and modulates mitochondrial integrity. Therefore, TRAP1 is a commander of tumor cells to control mitochondrial metabolism and cell death programs. Solid tumor has hypoxic regions where oxygen concentration is lower than normal healthy condition. Rapidly growing cancer cells often experience hypoxia due to insufficient vascular networks. As an adaptation mechanism, cancer cells reprogram their cellular metabolism which not only supports energy production of cancer cells but also stimulates various tumorigenic pathways. Here, we focused on the transcriptional regulation by hypoxia inducible factor 1 (HIF1) and modification of ATP synthase activity by ATPase inhibitory factor 1 (IF1). Both of them were regulated by the mitochondrial chaperone TRAP1 and coordinated retrograde signaling from mitochondria to nucleus. In Research 1, we observed that TRAP1 regulates hypoxia inducible factor 1α (HIF1α) under acute hypoxic condition. HIF1α is the key transcription factor to promote adaptation under hypoxia through up-regulating HIF1α target genes including tumor metabolism (PDK1, ALDOLC), autophagy (BNIP3), and angiogenesis (VEGF, SDF-1, CXCR4). It is widely known that HIF-1α protein accumulates during hypoxia with the effect of inhibition of oxygen dependent degradation through the von Hippel Lindau protein (pVHL) pathway. However, our data shows that suppression of TRAP1 downregulates HIF1α via pVHL-independent mechanisms. We presumed Glycogen synthase kinase 3 β (GSK3β) is a potential regulator of HIF1α degradation by protein phosphorylation. Collectively, we suggest a novel retrograde regulatory mechanism coordinated by TRAP1, GSK3β, and HIF1α under hypoxic condition. Many human tumors overexpress the mitochondrial ATPase inhibitory factor 1(IF1) which is activated under acidic or hypoxic environment. Activated IF1 binds to ATP synthase to block the ATP hydrolysis activity of it, therefore protects energy depletion in cancer cells to survive under metabolic stress condition. However, role of IF1 under hypoxia condition is not well known. In Research 2, I presented that TRAP1 regulates IF1 functions to modify the ATP synthase activity under hypoxia. TRAP1 directly bound to IF1, and inhibition of TRAP1 did not affect the protein stability of IF1 but down-regulate its activity under acute hypoxic condition. TRAP1 might interrupt homo-dimerization of IF1 to blocking activation. Overall, we demonstrated TRAP1 could directly regulate ATP synthase via IF1 under acute hypoxia. TRAP1 has already been considered a novel target protein for the development of cancer therapies. Glioblastoma (GBM) is hard to cure because there are no other options except the surgery and radiation treatment. In addition, Hypoxic conditions in the central part of GBM are the major factors increasing drug resistance and risk of relapse. Therefore, through this research we will investigate the new regulation pathways in GBM and expected to develop innovative therapeutic way based on my study.