%0 Journal Article
%T Targeting the Oncogenic E3 Ligase Skp2 in Prostate and Breast Cancer Cells with a Novel Energy Restriction-Mimetic Agent
%A Shuo Wei
%A Po-Chen Chu
%A Hsiao-Ching Chuang
%A Wen-Chun Hung
%A Samuel K. Kulp
%A Ching-Shih Chen
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0047298
%X Substantial evidence supports the oncogenic role of the E3 ubiquitin ligase S-phase kinase-associated protein 2 (Skp2) in many types of cancers through its ability to target a broad range of signaling effectors for ubiquitination. Thus, this oncogenic E3 ligase represents an important target for cancer drug discovery. In this study, we report a novel mechanism by which CG-12, a novel energy restriction-mimetic agent (ERMA), down-regulates the expression of Skp2 in prostate cancer cells. Pursuant to our previous finding that upregulation of ¦Â-transducin repeat-containing protein (¦Â-TrCP) expression represents a cellular response in cancer cells to ERMAs, including CG-12 and 2-deoxyglucose, we demonstrated that this ¦Â-TrCP accumulation resulted from decreased Skp2 expression. Evidence indicates that Skp2 targets ¦Â-TrCP for degradation via the cyclin-dependent kinase 2-facilitated recognition of the proline-directed phosphorylation motif 412SP. This Skp2 downregulation was attributable to Sirt1-dependent suppression of COP9 signalosome (Csn)5 expression in response to CG-12, leading to increased cullin 1 neddylation in the Skp1-cullin1-F-box protein complex and consequent Skp2 destabilization. Moreover, we determined that Skp2 and ¦Â-TrCP are mutually regulated, providing a feedback mechanism that amplifies the suppressive effect of ERMAs on Skp2. Specifically, cellular accumulation of ¦Â-TrCP reduced the expression of Sp1, a ¦Â-TrCP substrate, which, in turn, reduced Skp2 gene expression. This Skp2-¦Â-TrCP-Sp1 feedback loop represents a novel crosstalk mechanism between these two important F-box proteins in cancer cells with aberrant Skp2 expression under energy restriction, which provides a proof-of-concept that the oncogenic Csn5/Skp2 signaling axis represents a ¡°druggable¡± target for this novel ERMA.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0047298