Abstract
Abstract Heat shock protein 90 (HSP90) is an exciting target in cancer therapy. Our previous studies indicated that repair protein Rad51 involved in protecting non-small lung cancer (NSCLC) cell lines against chemotherapeutic agents induced cytotoxicity. In this study, the role of Rad51 expression in HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) induced cytotoxicity in two NSCLC cell lines, A549 and H1975, were investigated. 17-AAG treatment decreased cellular Rad51 protein and mRNA levels and phosphorylated MKK1/2-ERK1/2 protein levels. 17-AAG treatment disrupted the HSP90 and Rad51 interaction and triggered Rad51 protein degradation through 26S proteasome pathway. Moreover, 17-AAG treatment decreased DNA repair capacity in NSCLC cells, which could restore by enforced expression of Flag-Rad51 vector. Specific inhibition of Rad51 expression by siRNA could further enhance the 17-AAG-induced cytotoxicity. Enhancement of ERK1/2 activation by constitutively active MKK1/2 (MKK1/2-CA) vector significantly restored the 17-AAG-reduced Rad51 protein levels as well as cell viability. Moreover, arachidin-1, antioxidant stilbenoids, has demonstrated beneficial effects on human health. It could further decrease Rad51 expression and augment the cytotoxic effect and growth inhibition by 17-AAG. Moreover, 17-AAG and arachidin-1-induced synergistic cytotoxic effect and DNA repair capacity decrease could be abrogated in lung cancer cells with MKK1/2-CA or Flag-Rad51 expression vector transfection. Our results suggested that HSP90 inhibition induced cytotoxicity via downregulation of Rad51 expression and DNA repair capacity in NSCLC cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2554. doi:1538-7445.AM2012-2554
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