title: 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.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Chan
authors.forename: John Kenneth
authors.initials: JK
authors.lastname: Morrow
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Jin
authors.forename: Asad
authors.initials: A
authors.lastname: Moten
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Stagg
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cai
authors.forename: Dazhi
authors.initials: D
authors.lastname: Xu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Shuxing
authors.initials: S
authors.lastname: Zhang
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D016158:Genes, p53; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009097:Multienzyme Complexes; D044786:S-Phase Kinase-Associated Proteins; D054852:Small Molecule Libraries; D044767:Ubiquitin-Protein Ligases
references.citation: Nature. 2000 Nov 16;408(6810):381-6
references.pmid: 11099048
references.citation: J Biol Chem. 2003 Jul 11;278(28):25752-7
references.pmid: 12730199
references.citation: Semin Cancer Biol. 2009 Feb;19(1):25-31
references.pmid: 19130886
references.citation: Semin Cancer Biol. 2010 Apr;20(2):116-24
references.pmid: 20219680
references.citation: Blood. 2008 May 1;111(9):4690-9
references.pmid: 18305219
references.citation: Cancer Res. 2004 Jun 1;64(11):3892-9
references.pmid: 15172999
references.citation: Bioorg Med Chem. 2011 Mar 15;19(6):2046-54
references.pmid: 21353784
references.citation: Nat Cell Biol. 2010 May;12(5):457-67
references.pmid: 20383141
references.citation: Nat Rev Drug Discov. 2008 Dec;7(12):979-87
references.pmid: 19043449
references.citation: Mol Cell. 2003 May;11(5):1177-88
references.pmid: 12769843
references.citation: Dev Cell. 2004 May;6(5):661-72
references.pmid: 15130491
references.citation: J Biol Chem. 2012 Jan 2;287(1):245-256
references.pmid: 22065587
references.citation: Cell. 2012 May 25;149(5):1098-111
references.pmid: 22632973
references.citation: Cell. 2012 Jan 20;148(1-2):259-72
references.pmid: 22225612
references.citation: Science. 2009 Aug 28;325(5944):1134-8
references.pmid: 19713527
references.citation: Int J Bioinform Res Appl. 2009;5(3):269-79
references.pmid: 19525200
references.citation: ScientificWorldJournal. 2010 Jun 01;10:1001-15
references.pmid: 20526532
references.citation: Mol Cell. 2002 Dec;10(6):1511-8
references.pmid: 12504025
references.citation: Clin Cancer Res. 2010 Jan 1;16(1):154-63
references.pmid: 20048334
references.citation: J Mol Med (Berl). 2011 Sep;89(9):857-67
references.pmid: 21594579
references.citation: J Comput Aided Mol Des. 2007 Jan-Mar;21(1-3):97-112
references.pmid: 17340042
references.citation: BMC Bioinformatics. 2008 Feb 27;9:126
references.pmid: 18304355
references.citation: Nature. 2009 Apr 9;458(7239):732-6
references.pmid: 19360080
references.citation: Chem Biol. 2012 Dec 21;19(12):1515-24
references.pmid: 23261596
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Cancer. 2008 Apr 1;112(7):1415-24
references.pmid: 18260093
references.citation: Nat Genet. 2010 Jan;42(1):83-8
references.pmid: 19966802
references.citation: Methods Enzymol. 2005;398:125-42
references.pmid: 16275325
references.citation: J Biol Chem. 2007 Jan 19;282(3):2038-46
references.pmid: 17082193
references.citation: Nat Cell Biol. 1999 Aug;1(4):193-9
references.pmid: 10559916
references.citation: Nature. 2002 Apr 18;416(6882):703-9
references.pmid: 11961546
references.citation: Cancer Sci. 2003 Apr;94(4):344-9
references.pmid: 12824902
references.citation: Nat Cell Biol. 2009 Apr;11(4):420-32
references.pmid: 19270694
references.citation: Nat Rev Cancer. 2008 Jun;8(6):438-49
references.pmid: 18500245
references.citation: Mol Cell. 2003 May;11(5):1189-200
references.pmid: 12769844
references.citation: Methods Mol Biol. 2011;716:23-38
references.pmid: 21318898
references.citation: Bioorg Med Chem. 2009 Oct 1;17(19):6983-92
references.pmid: 19734051
references.citation: Stem Cell Rev. 2008 Sep;4(3):211-6
references.pmid: 18663609
references.citation: Nature. 2010 Mar 18;464(7287):374-9
references.pmid: 20237562