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: Hiroshi Yamaki, Motowo Nakajima, Kumiko W Shimotohno, Nobuo Tanaka
• Journal: The Journal of antibiotics (J Antibiot (Tokyo)) Vol. 64 Issue 9 Pg. 635-44 (Sep 2011) ISSN: 1881-1469 [Electronic] England
• PMID: 21811259 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Retinoblastoma Protein
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Cycle (genetics)
• Gene Expression Regulation, Neoplastic
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Neoplasms (drug therapy, genetics, pathology)
• Retinoblastoma Protein (genetics)
• Signal Transduction (genetics)
• Tumor Suppressor Protein p53 (genetics)
• Tumor Suppressor Proteins (genetics)