Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression.

Abstract

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.

• Authors: Chia-Hsin Chan, John Kenneth Morrow, Chien-Feng Li, Yuan Gao, Guoxiang Jin, Asad Moten, Loren J Stagg, John E Ladbury, Zhen Cai, Dazhi Xu, Christopher J Logothetis, Mien-Chie Hung, Shuxing Zhang, Hui-Kuan Lin
• Journal: Cell (Cell) Vol. 154 Issue 3 Pg. 556-68 (Aug 01 2013) ISSN: 1097-4172 [Electronic] United States
• PMID: 23911321 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Multienzyme Complexes
• S-Phase Kinase-Associated Proteins
• Small Molecule Libraries
• Ubiquitin-Protein Ligases

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Disease Models, Animal
• Drug Discovery
• Drug Screening Assays, Antitumor
• Genes, p53
• Glycolysis (drug effects)
• Humans
• Mice
• Mice, Nude
• Models, Molecular
• Multienzyme Complexes (antagonists & inhibitors, chemistry, metabolism)
• Neoplasm Transplantation
• Neoplasms (drug therapy, enzymology, genetics)
• Neoplastic Stem Cells (drug effects, metabolism)
• S-Phase Kinase-Associated Proteins (antagonists & inhibitors, chemistry, metabolism)
• Small Molecule Libraries
• Structure-Activity Relationship
• Transplantation, Heterologous
• Ubiquitin-Protein Ligases (antagonists & inhibitors, chemistry, metabolism)