TY - JOUR
T1 - XPharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression
AU - Chan, Chia Hsin
AU - Morrow, John Kenneth
AU - Li, Chien Feng
AU - Gao, Yuan
AU - Jin, Guoxiang
AU - Moten, Asad
AU - Stagg, Loren J.
AU - Ladbury, John E.
AU - Cai, Zhen
AU - Xu, Dazhi
AU - Logothetis, Christopher J.
AU - Hung, Mien Chie
AU - Zhang, Shuxing
AU - Lin, Hui Kuan
N1 - Funding Information:
We thank Dr. B.A. Schulman for reagents and Dr. David Hawke at the Proteomics Facility of the University of Texas MD Anderson Cancer Center (MDACC) for the support of LC-MS/MS analysis. The pharmacokinetic analysis was supported in part by MDACC support grant CA016672, with special thanks to the Pharmacology and Analytical Facility. This work was supported by the MDACC Trust Scholar Award, the MDACC Prostate SPORE development award (P50 CA140388), National Institutes of Health grants (to H.K.L.), grant IRG-08-061-01 from the American Cancer Society, MDACC Prostate SPORE career award, MDACC-UT Austin CTT-TI3D grants (to S.Z.), and MDACC Breast SPORE career development award and Susan G. Komen Foundation postdoctoral fellowship award (PDF12230504, to C.H.C.).
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2013.06.048
DO - 10.1016/j.cell.2013.06.048
M3 - Article
C2 - 23911321
AN - SCOPUS:84881192827
SN - 0092-8674
VL - 154
SP - X556-568
JO - Cell
JF - Cell
IS - 3
ER -