Fig. 2.

Heat shock protein 90 (HSP90) chaperons many onco-proteins driving cancer hallmarks. Endoplasmic reticulum (ER) is more oxidative, and cytosol, nucleus, and mitochondria are more reductive. HSP90 contributes in adjusting proteostasis to the redox environment in each cellular compartment, aberrant regulation of which leads to cancer hallmarks. ① HSP90 chaperons receptor tyrosine kinases (RTKs), non-receptor tyrosine kinase (Src), and primary mediators of the mitogen-activated protein kinase (MAPK) pathway such as rapidly accelerated fibrosarcoma (Raf), towards uncontrolled cell proliferation. ② Many proteins driving cells to escape various death signals such as glutathione peroxidase 4 (GPX4) in ferroptosis, mixed lineage kinase domain-like (MLKL) in necroptosis, cellular FADD-like IL-1β-converting enzyme-inhibitory protein (c-FLIP) in apoptosis,Unc-51 like autophagy activating kinase 1 (ULK1) in autophagy, and cyclin-dependent kinases (CDKs) such as CDK4 are chaperoned by HSP90. ③ HSP90 stabilizes hypoxia-inducible factor 1 alpha (HIF1α) under hypoxia that induces several key enzymes involved in glycolysis such as hexokinase 2 (HKII), phosphofructokinase 1 (PFK1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and lactate dehydrogenase alpha (LDHA), as well as modulates the stability and activity of v-myc avian myelocytomatosis viral oncogene homologue (c-Myc) that regulates the expression of several glycolytic enzymes such as LDHA and pyruvate kinase muscle isozyme 2 (PKM2), leading to aerobic glycolysis and metabolic reprogramming. ④ HSP90 chaperons major histocompatibility complex class I (MHC-I) to enable cells with the ability of evading immune surveillance. ⑤ HSP90 chaperons vascular endothelial growth factor (VEGFR) family members and key components of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/endothelial nitric oxide synthase (eNOS) pathway such as eNOS and AKT to enable tumor angiogenesis. ⑥ HSP90 promotes tumor metastasis by chaperoning extracellular matrix proteins such as matrix metallopeptidase 2 (MMP2), MMP7, MMP9, as well as epithelial mesenchymal transition (EMT)-related tanscniption factor (TF) reactive oxygen species (ROS). ⑦ HSP90 promotes cancer-associated inflammation by chaperoning several pro-inflammatory proteins such as toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB). ⑧ HSP90 activates DNA polymerase-η, interrogating genome integrity. APC: antigen presentation cell; ERK: extracellular regulated protein kinase; MAPKK: mitogen-activated protein kinase (MAPK) kinase; PDK1: pyruvate dehydrogenase kinase 1; Ras: rat sarcoma viral oncogene homologue.