Abstract
HSP70 and HSP90 are two powerful chaperone machineries involved in survival and proliferation of tumor cells. Residing in various cellular compartments, HSP70 and HSP90 perform specific functions. Concurrently, HSP70 and HSP90 homologs may also translocate from their primary site under various stress conditions. Herein, we address the current literature on the role of HSP70 and HSP90 chaperone networks in cancer. The goal is to provide a comprehensive review on the functions of cytosolic, mitochondrial and endoplasmic reticulum HSP70 and HSP90 homologs in cancer. Given that high expression of HSP70 and HSP90 enhances tumor development and associates with tumor aggressiveness, further understanding of HSP70 and HSP90 chaperone networks may provide clues for the discoveries of novel anti-cancer therapies.
Highlights
Heat shock protein 70 kDa (HSP70) and HSP90 are two powerful ATPase-dependent chaperone machineries involved in protein folding, degradation, maturation of client proteins and protein trafficking [1,2,3,4]
Joshi and colleagues demonstrated that Tumor necrosis factor receptor-associated protein 1 (TRAP1) interacts with other mitochondrial chaperones, including HSPA9/GRP75, HSP60 and prohibitin as well as with OXPHOSassociated molecules, such as complex IV, complex II and ATP synthase [117]
GRP94 and GRP78 are endoplasmic reticulum (ER) HSP90 and HSP70 members, which play an important role in the regulation of apoptosis, invasion, metastasis, autophagy, drug resistance, cancer cell stemness and tumor immunity
Summary
Heat shock protein 70 kDa (HSP70) and HSP90 are two powerful ATPase-dependent chaperone machineries involved in protein folding, degradation, maturation of client proteins and protein trafficking [1,2,3,4]. Joshi and colleagues demonstrated that TRAP1 interacts with other mitochondrial chaperones, including HSPA9/GRP75, HSP60 and prohibitin as well as with OXPHOSassociated molecules, such as complex IV, complex II and ATP synthase [117]. Li and colleagues demonstrated that high expression of GRP78 activates the Class III phosphatidylinositol 3-kinase (PI3K)-mediated autophagy pathway and induces degradation of IKKb, leading to inhibition of the NF-kB pathway, at the same time altering expression of pyruvate kinase M2 and HIF-1a [176] Along this line, under stress conditions, GRP78 binds to cytosolic misfolded proteins and SQSTM1/p62 [171, 177, 178]. GRP78s may change its location and mediate various processes, including UPR, Warburg phenotype, stemness, apoptosis, autophagy and innate immune responses
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