Abstract
Abstract D,L-Sulforaphane (SFN), a synthetic racemic analogue of broccoli constituent L-sulforaphane, inhibits chemically-induced cancer in experimental rodents. SFN administration also suppresses cancer development in transgenic mouse models. Anticancer effect of SFN is associated with apoptosis induction but the mechanism of cell death is not fully understood. Using MDA-MB-231 (an estrogen-independent cell line) and MCF-7 (an estrogen-responsive cell line) human breast cancer cells as a model, we now demonstrate that the SFN-induced apoptosis is regulated by growth factor adapter protein p66Shc. Exposure of MDA-MB-231 and MCF-7 cells to SFN resulted in increased Ser36 phosphorylation of p66Shc. Immortalized mouse embryonic fibroblasts derived from p66Shc knockout mouse were significantly more resistant to SFN-mediated growth inhibition (judged by trypan blue dye exclusion assay) and apoptosis induction (judged by cytoplasmic histone-associated apoptotic DNA fragmentation) compared with embryonic fibroblasts from wild-type mouse. Moreover, transient transfection of MDA-MB-231 and MCF-7 cells with p66Shc-targeted siRNA conferred significant protection against SFN-induced cytoplasmic histone-associated DNA fragmentation. Protein level of prolyl isomerase 1 (Pin1), a protein implicated in mitochondrial translocation of p66Shc, was decreased on a 24-hour treatment with SFN in both MDA-MB-231 and MCF-7 cells. However, apoptosis induction resulting from SFN exposure was not affected by ectopic expression of Pin1 (MCF-7). In conclusion, the present study provides novel insights into the molecular circuitry of SFN-induced apoptosis involving p66Shc. This investigation was supported by the USPHS grant RO1 CA115498-05, 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 866. doi:10.1158/1538-7445.AM2011-866
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