Targeting the p27 E3 ligase SCF(Skp2) results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy.
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.
Chen
Qing
Q
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, USA.
Xie
Weilin
W
Kuhn
Deborah J
DJ
Voorhees
Peter M
PM
Lopez-Girona
Antonia
A
Mendy
Derek
D
Corral
Laura G
LG
Krenitsky
Veronique Plantevin
VP
Xu
Weiming
W
Moutouh-de Parseval
Laure
L
Webb
David R
DR
Mercurio
Frank
F
Nakayama
Keiichi I
KI
Nakayama
Keiko
K
Orlowski
Robert Z
RZ
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*
D000970:Antineoplastic Agents; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044767:Ubiquitin-Protein Ligases