Fig. 5

Illustration of HSPs in the Other Hallmarks of Cancer. a HSPs in inducting angiogenesis. Under hypoxic conditions, hypoxia-inducible factor degradation is inhibited. Accumulated HIF-α translocates to the nucleus, activating transcription that leads to the secretion of multiple pro-angiogenic factors (e.g., VEGF, IGF) and downstream signaling pathways, thereby promoting vascular growth. HSP90 contributes to angiogenesis by enhancing the protein stability of HIF-α, preventing its degradation, and modulating the activity of proteins such as STAT3 and AKT. Additionally, GRP78 has been implicated in vascular growth. b HSPs in activating tumor invasion and metastasis. Signaling pathways (e.g., EGF, FGF) activate downstream transcription factors regulating EMT, leading to loss of epithelial polarity and increased mobility. Multiple HSPs, including HSP90, HSP70, HSP40, and HSP27, promote the EMT process by modulating transmembrane receptor tyrosine kinases (e.g., EGFR, FGFR), transcription factors (e.g., TWIST1, Slug), and calcium-dependent adhesion proteins (e.g., E-cadherin, N-cadherin). c HSPs in reprogramming energy metabolism. Under aerobic conditions, normal cells metabolize glucose via glycolysis in the cytoplasm to produce pyruvate, which then undergoes oxidative phosphorylation in the mitochondria to generate energy. Under anaerobic conditions, oxidative phosphorylation in normal cells decreases, and glycolysis produces energy. In tumor cells, regardless of oxygen, there is a tendency to produce energy through glycolysis, known as aerobic glycolysis. HSPs regulate critical factors involved in the metabolism of tumor cells. Indeed, HSP90 achieves metabolic reprogramming in tumor cells by interacting with various proteins, including PKM2, HK2, and PFKP. TRAP1 stabilizes HIF-1α by inhibiting SDH, promoting tumor progression. HSP60 supports tumor metabolism via DLST and mitochondrial integrity. d HSP90 in evading immune destruction. Dendritic cells take up extracellular antigens in the cell. The internalized antigens bind with HSP90 and are then released into the cytoplasm, ultimately degraded through the proteasome pathway