Hsp90 (Heat-shock protein 90) plays a key role in regulating the physiology of cells exposed to environmental stress and in maintaining the malignant phenotype of tumor cells.
Cancer cells grow in an environment of hypoxia, low pH, and low-nutrient concentration. The role of Hsp90 in maintaining the stability of proteins under stress may be necessary for cell viability under these conditions. Further, cancer cells often harbor mutated oncogenic proteins. Some of these are gain-of-function mutations that are required for the transformed phenotype. Hsp90 may be required for maintaining the folded, functionally active conformation of these proteins. In addition, activation of signaling pathways mediated by steroid receptors, Raf, and other Hsp90 targets is necessary for the growth and survival of many tumors, which thus probably also require functional Hsp90.
Hsp90 contains a conserved pocket in its amino-terminus that binds ATP and ADP with low affinity. Completion of Hsp90-dependent protein refolding is ATP-dependent and involves dissociation of the renaturated protein from the chaperone complex. Ansamycin antibiotics and radicicol are natural products that bind to the Hsp90 pocket and alter its function. Exposure of cells to these compounds results in the degradation of a subset of signaling proteins that associate with Hsp90, including steroid receptors and the Raf serine kinase, as well as certain transmembrane tyrosine kinases, including HER2 and met.
Treatment with ansamycins results in a G1 cell cylce arrest followed by differentiation and apoptosis. Ansamycins cause RB-dependent cell cycle arrest associated with loss of D-cyclin and hypophosphorylaton of RB. Ansamycins decrease D-cyclin levels by downregulating a PI3 kinase, Akt-dependent pathway required for their expression. Downregulation of D-cyclin was due, in part, to loss of Akt expression in response to drug. Moreover, in HER2-overexpressing breast cancer cells, 17-AAG caused rapid inhibition of Akt activity prior to any change in Akt protein.
17-AAG treatment of mice bearing breast or prostate tumor xenografts results in dose-dependent growth inhibition of the tumor. Treatment, at doses tolerable to the host, results in a decline in androgen receptor and HER2 expression and inactivation of Akt. These data support the clinical development of ansamycins for the treatment of advanced breast and prostate cancer.