title: Targeting the p27 E3 ligase SCF(Skp2) results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy.
abstract: Decreased p27(Kip1) levels are a poor prognostic factor in many malignancies, and can occur through up-regulation of SCF(Skp2) E3 ligase function, resulting in enhanced p27 ubiquitination and proteasome-mediated degradation. While proteasome inhibitors stabilize p27(Kip1), agents inhibiting SCF(Skp2) may represent more directly targeted drugs with the promise of enhanced efficacy and reduced toxicity. Using high-throughput screening, we identified Compound A (CpdA), which interfered with SCF(Skp2) ligase function in vitro, and induced specific accumulation of p21 and other SCF(Skp2) substrates in cells without activating a heat-shock protein response. CpdA prevented incorporation of Skp2 into the SCF(Skp2) ligase, and induced G(1)/S cell-cycle arrest as well as SCF(Skp2)- and p27-dependent cell killing. This programmed cell death was caspase-independent, and instead occurred through activation of autophagy. In models of multiple myeloma, CpdA overcame resistance to dexamethasone, doxorubicin, and melphalan, as well as to bortezomib, and also acted synergistically with this proteasome inhibitor. Importantly, CpdA was active against patient-derived plasma cells and both myeloid and lymphoblastoid leukemia blasts, and showed preferential activity against neoplastic cells while relatively sparing other marrow components. These findings provide a rational framework for further development of SCF(Skp2) inhibitors as a novel class of antitumor agents.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Weilin
authors.initials: W
authors.lastname: Xie
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Kuhn
authors.forename: Peter M
authors.initials: PM
authors.lastname: Voorhees
authors.forename: Antonia
authors.initials: A
authors.lastname: Lopez-Girona
authors.forename: Derek
authors.initials: D
authors.lastname: Mendy
authors.forename: Laura G
authors.initials: LG
authors.lastname: Corral
authors.forename: Veronique Plantevin
authors.initials: VP
authors.lastname: Krenitsky
authors.forename: Weiming
authors.initials: W
authors.lastname: Xu
authors.forename: Laure
authors.initials: L
authors.lastname: Moutouh-de Parseval
authors.forename: David R
authors.initials: DR
authors.lastname: Webb
authors.forename: Frank
authors.initials: F
authors.lastname: Mercurio
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044767:Ubiquitin-Protein Ligases