HEAT SHOCK PROTEINS IN CANCER

CIOCCA DR

Montevideo

Conferencia; First Conference South American Chapter Cell Stress Society International; 2014

Cell Stress Society International

Most cancers overexpress several members of the HSPs, these proteins have been described as chaperones of tumorigenesis. Several reasons might explain the activation of HSF1 and the accumulation of HSPs during carcinogenesis permitting the malignant phenotype. For example HSF1 may be phosphorylated on serine 326 when cells are subjected to pro-malignant signaling, and activation in mammary cancer involves the receptor tyrosine kinases HER2 and HER3 and the cytoplasmic serine kinase phosphatidyl-inositol 3 kinase (PI-3 kinase). Moreover, the ?mutator phenotype? associated with cancer can cause the requirement for HSPs to chaperone the increased protein load that accompanies transformation (including mutant proteins). In term this may explain the application of HSP90 inhibitors in cancer therapy causing the depletion of a wide spectrum of oncogenes/oncoproteins (presumably due to unfolding and proteolysis) and inhibition of tumor growth. Overall HSF1 and HSPs have been implicated in most of ?the hallmarks of cancer? including: (1) maintenance of sustained proliferative signaling, (2) resisting cell death, (3) inhibition of replicative senescence, (4) induction of tumor angiogenesis, (5) activation of invasion and metastasis, (6) reprogramming of energy metabolism, and (7) evasion of immune destruction. The role of individual HSPs in cancer have been reviewed recently [Ciocca DR, Arrigo AP, Calderwood SK, Arch Toxicol 87(1):19-48 (2013)]. The HSF1/HSP system has diagnostic, prognostic, predictive, and treatment implications in cancer depending on the type of malignancy, the HSP analyzed and the molecular context.