title: Molecular basis for the actions of Hsp90 inhibitors and cancer therapy.
abstract: Heat-shock protein 90 (Hsp90) inhibitor downregulates c-Myc expression and upregulates the expression of tumor repressor proteins 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 complex with the phosphorylation of pRB by cyclin-cyclin-dependent kinase (CDK) complexes. The released E2F promotes the transcription of target genes involved in cell cycle progression. The pRB/E2F signaling pathway is controlled by DNA methyltransferase-1 (Dnmt-1). The elevated expression of Dnmt-1 has been reported in carcinomas of the colon, lung and prostate. 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 Hsp90 inhibitors that show promise for cancer therapy are summarized.
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan. h_yamaki@castle.ocn.ne.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaki
authors.forename: Motowo
authors.initials: M
authors.lastname: Nakajima
authors.forename: Kumiko W
authors.initials: KW
authors.lastname: Shimotohno
authors.forename: Nobuo
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins