Molecular basis for the actions of Hsp90 inhibitors and cancer therapy.

Heat-shock protein 90 (Hsp90) inhibitor downregulates c-Myc expression and upregulates the expression of tumor repressorproteins such as p53 and pRB, inhibiting the G1/S transition and causing G2/M arrest during cell cycle progression.The cycle progression is extensively controlled by the pRB/E2F signaling pathway. E2F is released from the pRB/E2F complexwith the phosphorylation of pRB by cyclin–cyclin-dependent kinase (CDK) complexes. The released E2F promotes thetranscription of target genes involved in cell cycle progression. The pRB/E2F signaling pathway is controlled by DNAmethyltransferase-1 (Dnmt-1). The elevated expression of Dnmt-1 has been reported in carcinomas of the colon, lung andprostate. A defect of pRB expression in Rb / cancer cells is caused by the aberrant methylation of CpG in the Rb promoter.The Hsp90 inhibitor disrupts the Dnmt-1/Hsp90 association and upregulates pRB expression. In this review, the Hsp90inhibitors that show promise for cancer therapy are summarized.The Journal of Antibiotics (2011) 64, 635–644; doi:10.1038/ja.2011.60; published online 3 August 2011Keywords: cancer therapy; Hsp90 inhibitor; signal-transduction pathwayINTRODUCTIONFunction of heat-shock proteinHeat-shock protein (Hsp) is an ubiquitous molecular chaperonedistributed from bacteria to animal cells. Hsp is involved in post-translational folding, stability and protein maturation. Hsp is anessential mediator of signal-transduction and cell cycle progressionin prokaryotes and eukaryotes. Numerous Hsps including the Hsp60,Hsp70 and Hsp90 families are distributed throughout cytoplasm,mitochondria, nucleolus and cytoplasmic membrane. Human Hsp90includes 17 genes classified as HSP90AA, HSP90AB, HSP90B andTRAP.