Background: 17-allylamino-demethoxy geldanamycin (17-AAG) inhibits the chaperone function of heat shock protein 90 (Hsp90) and promotes the proteasomal degradation of its client proteins. 17AAG also induced the mitochondrial release, accumulation of mitochondrial-derived activator of caspases, resulting in apoptosis. 17-AAG is currently in development for the treatment of cancer. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate expression of many genes and play a significant role in cancer and possibly in Hsp90 signaling. Therefore, a screen of miRNA mimics and inhibitors was conducted for chemosensitization to 17-AAG.

Methods: To identify individual microRNAs that synergizes with 17AAG, microRNA libraries were screened for apoptotic activity against HT29 cells when co-treated with 17AAG. The microRNAs were transfected into HT29 cells 48 hrs before treatment with 17AAG. After 72 hrs of 17AAG exposure, apoptosis was quantitated by the release of caspase 3/7. The effects of these miRNA on cellular protein, mRNA, and miRNA profile were also examined using microarray technology.

Results: Four miRNAs were identified which had potent chemosensitization effect on cells exposed to 17-AAG. These miRNA are different in sequence and did not synergize with one another. Alone they did not induce apoptosis; however, when combined with 17-AAG, they increased the apoptotic activity of 17-AAG up to 4 folds. Possible mechanism of action for these miRNAs was examined by microarray analysis which suggested that they act on the Hsp90/70 pathway to enhance the activity of 17-AAG.

Conclusions: Four miRNAs were identified as chemosensitizers for 17-AAG. These miRNAs could provide the basis for determination of tumor types that will be sensitive to 17-AAG, as well as a potential biomarker for predicting 17-AAG effectiveness.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4040.