Pharmacological Inactivation of Skp2 SCF Ubiquitin Ligase Restricts Cancer Stem Cell Traits and Cancer Progression

作者：Chan Chia Hsin; Morrow John Kenneth; Li Chien Feng; Gao Yuan; Jin Guoxiang; Moten Asad; Stagg Loren J; Ladbury John E; Cai Zhen; Xu Dazhi; Logothetis Christopher J; Hung Mien Chie; Zhang Shuxing^*; Lin Hui Kuan

来源：Cell, 2013, 154(3): 556-568.

DOI：10.1016/j.cell.2013.06.048

Skp2 E3 ligase is overexpressed in numerous human cancers and plays a critical role in cell-cycle progression, senescence, metabolism, cancer progression, and metastasis. In the present study, we identified a specific Skp2 inhibitor using high-throughput in silico screening of large and diverse chemical libraries. This Skp2 inhibitor selectively suppresses Skp2 E3 ligase activity, but not activity of other SCF complexes. It also phenocopies the effects observed upon genetic Skp2 deficiency, such as suppressing survival and Akt-mediated glycolysis and triggering p53-independent cellular senescence. Strikingly, we discovered a critical function of Skp2 in positively regulating cancer stem cell populations and self-renewal ability through genetic and pharmacological approaches. Notably, Skp2 inhibitor exhibits potent antitumor activities in multiple animal models and cooperates with chemotherapeutic agents to reduce cancer cell survival. Our study thus provides pharmacological evidence that Skp2 is a promising target for restricting cancer stem cell and cancer progression.

• 出版日期2013-8-1
• 单位中国医科大学