Gene and Protein Expression Profiling of Human Ovarian Cancer Cells Treated with the Heat Shock Protein 90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin

The Royal Marsden NHS Foundation Trust, Londinium, England, United Kingdom
Cancer Research (Impact Factor: 9.33). 05/2007; 67(7):3239-53. DOI: 10.1158/0008-5472.CAN-06-2968
Source: PubMed


The promising antitumor activity of 17-allylamino-17-demethoxygeldanamycin (17AAG) results from inhibition of the molecular chaperone heat shock protein 90 (HSP90) and subsequent degradation of multiple oncogenic client proteins. Gene expression microarray and proteomic analysis were used to profile molecular changes in the A2780 human ovarian cancer cell line treated with 17AAG. Comparison of results with an inactive analogue and an alternative HSP90 inhibitor radicicol indicated that increased expression of HSP72, HSC70, HSP27, HSP47, and HSP90beta at the mRNA level were on-target effects of 17AAG. HSP27 protein levels were increased in tumor biopsies following treatment of patients with 17AAG. A group of MYC-regulated mRNAs was decreased by 17AAG. Of particular interest and novelty were changes in expression of chromatin-associated proteins. Expression of the heterochromatin protein 1 was increased, and expression of the histone acetyltransferase 1 and the histone arginine methyltransferase PRMT5 was decreased by 17AAG. PRMT5 was shown to be a novel HSP90-binding partner and potential client protein. Cellular protein acetylation was reduced by 17AAG, which was shown to have an antagonistic interaction on cell proliferation with the histone deacetylase inhibitor trichostatin A. This mRNA and protein expression analysis has provided new insights into the complex molecular pharmacology of 17AAG and suggested new genes and proteins that may be involved in response to the drug or be potential biomarkers of drug action.

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Available from: Paul Andrew Clarke, Jan 09, 2014
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    • "In cell-based assays, proteomic techniques have been applied to profile expression-level changes, like histone modification enzymes, after treatment with a heat shock protein 90 inhibitor (HSP90). Maloney et al. suggested that similar analyses might aid pharmacology by illuminating genes and proteins involved in drug responses (71). Indeed, in ovarian cancer cells, histone de-acetylation at the RGS10-1 promoter correlates with suppression of RGS10 and chemoresistance (72). "
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    • "HSP90 inhibitors act by blocking the formation of complexes with multiple client proteins that contribute to tumorigenesis and cell growth, thereby blocking several distinct signaling pathways related to cell survival [35], [36]. The HSP90 inhibitor 17-AAG has been proven to have potent anti-tumor effects, but it can also promote the expression of compensatory HSPs that favor cell proliferation and survival [35]. As a consequence, these partially reduce 17-AAG’s anticancer effects. "
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    • "However, Hsc70/Hsp70 up-regulation or modified distribution did not compensate for the morphological changes generated by Hsp90 inhibition . Thus, while different chaperones can compensate each other functions in some cell types [23] [24], in neurons Hsc70/Hsp70 is unable to compensate Hsp90 functions in axonal polarization. "
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