BACKGROUND: p66Shc, an isoform of Shc adaptor proteins, mediates diverse signals, including cellular stress and mouse longevity. p66Shc protein level is elevated in several carcinomas and steroid-treated human cancer cells. Several lines of evidence indicate that p66Shc plays a critical role in steroid-related carcinogenesis, and steroids play a role in its elevated levels in those cells without known mechanism.
METHODS AND FINDINGS: In this study, we investigated the molecular mechanism by which steroid hormones up-regulate p66Shc protein level. In steroid-treated human prostate and ovarian cancer cells, p66Shc protein levels were elevated, correlating with increased cell proliferation. These steroid effects on p66Shc protein and cell growth were competed out by the respective antagonist. Further, actinomycin D and cyclohexamide could only partially block the elevated p66Shc protein level by steroids. Treatment with proteasomal inhibitors, but not lysosomal protease inhibitor, resulted in elevated p66Shc protein levels, even higher than that by steroids. Using prostate cancer cells as a model, immunoprecipitation revealed that androgens and proteasomal inhibitors reduce the ubiquitinated p66Shc proteins.
CONCLUSIONS: The data collectively indicate that functional steroid receptors are required in steroid up-regulation of p66Shc protein levels in prostate and ovarian cancer cells, correlating with cell proliferation. In these steroid-treated cells, elevated p66Shc protein level is apparently in part due to inhibiting its ubiquitination. The results may lead to an impact on advanced cancer therapy via the regulation of p66Shc protein by up-regulating its ubiquitination pathway.
Cell Line, Tumor, Cell Proliferation, Female, Humans, Male, Ovarian Neoplasms, Prostatic Neoplasms, Receptors, Steroid, Shc Signaling Adaptor Proteins, Steroids, Ubiquitination, Up-Regulation
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Kumar, Santosh; Kumar, Satyendra; Rajendran, Mythilypriya; Alam, Syed Mahfuzul; Lin, Fen-Fen; Cheng, Pi-Wan; and Lin, Ming-Fong, "Steroids up-regulate p66Shc longevity protein in growth regulation by inhibiting its ubiquitination." (2011). Journal Articles: Biochemistry & Molecular Biology. 41.