HSP90: Chaperone-me-not

With increasing understanding of the molecular basis of carcinogenesis, its progression and metastasis, the cancer therapy has shifted from empirical approaches to targeting specific molecules that regulate the complex network of signalling pathways for cell survival and proliferation. These include key players in malignant transformation like protein kinases, transcription factors, steroid hormone receptors, cell cycle regulators, signal transduction proteins and regulators of apoptosis. Almost all these proteins depend upon the molecular chaperone Hsp90 for their proper folding, stability and function and thus are a part of the Hsp90 clientele. Dependence of these proteins on Hsp90 makes this chaperone an appealing target for cancer therapeutics. Inhibition of Hsp90 can affect multiple oncogenic pathways simultaneously. Moreover Hsp90 inhibitors selectively kill cancer cells compared to normal cells and cancer cells have greater dependence on Hsp90 for the maintenance of intracellular protein homeostasis. All this has led to a rapid pace discovery of Hsp90 clients as well as chemical inhibitors of Hsp90. The role of hsp90 in cancer, tumor selectivity of Hsp90 inhibitors and the current status of Hsp90 inhibitors are discussed in the present review.