Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 113, Issue 2, Pages 599-610Publisher
WILEY
DOI: 10.1002/jcb.23386
Keywords
SULFORAPHANE; p66Shc; APOPTOSIS; CHEMOPREVENTION
Categories
Funding
- National Cancer Institute [R01 CA115498-06]
- United States Public Health Service [P30CA047904]
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Cancer chemopreventive response to D,L-sulforaphane (SFN), a synthetic racemic analogue of broccoli constituent L-sulforaphane, is partly attributable to apoptosis induction, but the mechanism of cell death is not fully understood. The present study demonstrates a critical role for adapter protein p66Shc in SFN-induced apoptosis. Immortalized mouse embryonic fibroblasts (MEF) derived from p66shc knockout mice were significantly more resistant to SFN-induced apoptosis, collapse of mitochondrial membrane potential, and reactive oxygen species (ROS) production compared with MEF obtained from the wild-type mice. Notably, a spontaneously immortalized and non-tumorigenic human mammary epithelial cell line (MCF-10A) was resistant to SFN-induced ROS production and apoptosis. Stable overexpression of manganese superoxide dismutase in MCF-7 and MDA-MB-231 human breast cancer cells conferred near complete protection against SFN-induced apoptosis and mitochondrial membrane potential collapse. SFN treatment resulted in increased S36 phosphorylation and mitochondrial translocation of p66shc in MDA-MB-231 and MCF-7 cells, and SFN-induced apoptosis was significantly attenuated by RNA interference of p66shc in both cells. SFN-treated MDA-MB-231 and MCF-7 cells also exhibited a marked decrease in protein level of peptidyl prolyl isomerase (Pin1), which is implicated in mitochondrial translocation of p66shc. However, stable overexpression of Pin1 failed to alter proapoptotic response to SFN at least in MCF-7 cells. Finally, SFN-induced S36 phosphorylation of p66Shc was mediated by protein kinase C beta (PKC beta), and pharmacological inhibition of PKC beta significantly inhibited apoptotic cell death resulting from SFN exposure. In conclusion, the present study provides new insight into the mechanism of SFN-induced apoptosis involving PKC beta -mediated S36 phosphorylation of p66shc. J. Cell. Biochem. 113: 599610, 2012. (C) 2011 Wiley Periodicals, Inc.
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