Abstract
Abstract Her2 is a well established marker of breast cancer and found to be overexpressed in around 20-30% of cases. It plays role in cell proliferation, angiogenesis, metastasis and drug resistance leading to poor prognosis and survival. Therefore development of novel agents targeting Her2 is highly imminent. Based on several epidemiological and experimental evidences, isothiocyanates have been shown to have anticancer effects. We evaluated the effect of phenethyl isothiocyanate (PEITC) in breast cancer cells. Treatment with PEITC for 24h significantly suppressed the survival of both MCF-7 (estrogen dependent) and MDA-MB-231 (estrogen independent) cells in a concentration dependent manner with an IC50 of about 12µM and 8µM respectively. Substantial apoptosis by PEITC treatment was observed in both the cell lines. Interestingly, PEITC treatment after 24h drastically reduced Her2 expression. The decrease in Her2 expression by PEITC treatment correlated with the cleavage of Her2. The low molecular weight fragments of Her2 increased with increasing PEITC concentration. Caspase-3 specific inhibitor blocked PEITC-mediated cleavage of Her2 and apoptosis indicating the involvement of caspase-3 in the cleavage of Her2. Her2 fragments have been shown to induce mitochondria-mediated apoptosis. In agreement, our results show the cleavage of Bid and increase in Bax level, whereas the expression of Bcl-XL was down regulated. Further, PEITC treatment resulted in the release of cytochrome c from the mitochondria into the cytosol, activating caspase 9/3 and PARP cleavage. Taken togther, our results suggests that cleavage of Her2 by PEITC activates mitochondrial death pathway in breast cancer cells. Further mechanistic studies are in progress. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4624. doi:10.1158/1538-7445.AM2011-4624
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