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

• Published in: Cell Vol. 154; no. 3; pp. 556 - 568
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2013
• Subjects: animal models; Animals; antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; cell cycle; cell senescence; cell viability; cells; Disease Models, Animal; Drug Discovery; Drug Screening Assays, Antitumor; drug therapy; Genes, p53; glycolysis; Glycolysis - drug effects; Humans; ligases; metastasis; Mice; Mice, Nude; Models, Molecular; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - chemistry; Multienzyme Complexes - metabolism; Neoplasm Transplantation; neoplasms; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; population; S-Phase Kinase-Associated Proteins - antagonists & inhibitors; S-Phase Kinase-Associated Proteins - chemistry; S-Phase Kinase-Associated Proteins - metabolism; screening; senescence; Small Molecule Libraries; stem cells; Structure-Activity Relationship; Transplantation, Heterologous; ubiquitin-protein ligase; Ubiquitin-Protein Ligases - antagonists & inhibitors; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0092-8674; 1097-4172
• 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. [Display omitted] •Integrated computational approaches identify a specific Skp2 inhibitor•The Skp2 inhibitor selectively impairs Skp2 activity and functions•Skp2 inactivation restricts cancer stemness and potentiates chemotherapy sensitivity•The Skp2 inhibitor exhibits potent antitumor activity A selective Skp2 inhibitor identified through a virtual chemical screen suppresses cancer stem cell renewal and cancer progression, establishing Skp2 as a promising target for cancer treatment.