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Accession Number:
ADA566865
Title:
Investigating the Role of Akt1 in Prostate Cancer Development through Phosphorylation-dependent Regulation of Skp2 Stability and Oncogenic Function
Descriptive Note:
Final rept. 1 Sep 2009-31 Aug 2012
Corporate Author:
BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA
Report Date:
2012-09-01
Pagination or Media Count:
22.0
Abstract:
Elevated Skp2 expression is frequently observed in many tumors including breast and prostate carcinomas. However, the molecular mechanisms underlying elevated Skp2 expression in prostate cancers have not been fully explored. Hyperactivation of the Akt pathway is considered a hallmark of many cancers and it has been reported that activation of the PI3KAkt pathway enhances p27 destruction. Thus, we hypothesize that sustained Akt activity in prostate cancer cells leads to elevated phosphorylation of Skp2, and subsequently influences Skp2 stability and its oncogenic functions. In support of our hypothesis, we found that Skp2 abundance is affected by manipulation of the PTENPI3KAkt pathway in the PC3 and LNCaP prostate cancer cell lines. Furthermore, we showed that this is partially through phosphorylation of Skp2 by Akt, which impairs Skp2 destruction by Cdh1. Sequence analysis revealed that the Akt phosphorylation site Ser72 is localized in a putative Nuclear Localization Sequence NLS. Consistent with this notion, we found that overexpression of Myr-Akt promoted Skp2 cytoplasmic translocation, and that inhibition of PI3KAkt activity enhanced its nuclear localization. We believe that these studies will provide a novel mechanism for Skp2 overexpression in prostate cancers and provide the rationale for developing Akt1-specific inhibitors to treat prostate cancer patients.
Distribution Statement:
APPROVED FOR PUBLIC RELEASE
