Targeting the oncogenic E3 ligase Skp2 in prostate and breast cancer cells with a novel energy restriction-mimetic agent.

Abstract

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 β-transducin repeat-containing protein (β-TrCP) expression represents a cellular response in cancer cells to ERMAs, including CG-12 and 2-deoxyglucose, we demonstrated that this β-TrCP accumulation resulted from decreased Skp2 expression. Evidence indicates that Skp2 targets β-TrCP for degradation via the cyclin-dependent kinase 2-facilitated recognition of the proline-directed phosphorylation motif (412)SP. 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 β-TrCP are mutually regulated, providing a feedback mechanism that amplifies the suppressive effect of ERMAs on Skp2. Specifically, cellular accumulation of β-TrCP reduced the expression of Sp1, a β-TrCP substrate, which, in turn, reduced Skp2 gene expression. This Skp2-β-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.

• Authors: Shuo Wei, Po-Chen Chu, Hsiao-Ching Chuang, Wen-Chun Hung, Samuel K Kulp, Ching-Shih Chen
• Journal: PloS one (PLoS One) Vol. 7 Issue 10 Pg. e47298 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23071779 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Multiprotein Complexes
• S-Phase Kinase-Associated Proteins
• beta-Transducin Repeat-Containing Proteins
• Peptide Hydrolases
• COPS5 protein, human
• COP9 Signalosome Complex
• SIRT1 protein, human
• Sirtuin 1

Topics

• Binding Sites
• Breast Neoplasms (enzymology, metabolism)
• COP9 Signalosome Complex
• Cell Line, Tumor
• Energy Metabolism
• Feedback, Physiological
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Male
• Multiprotein Complexes (genetics, metabolism)
• Mutagenesis, Site-Directed
• Peptide Hydrolases (genetics, metabolism)
• Prostatic Neoplasms (enzymology, metabolism)
• S-Phase Kinase-Associated Proteins (genetics, metabolism, physiology)
• Sirtuin 1 (metabolism, physiology)
• beta-Transducin Repeat-Containing Proteins (chemistry, metabolism)