|
|
Blood, 1 May 2008, Vol. 111, No. 9, pp. 4690-4699.
Prepublished online as a Blood First Edition Paper on February 27, 2008; DOI 10.1182/blood-2007-09-112904.
 Previous Article | Next Article 
Submitted September 18, 2007
Accepted February 4, 2008
Targeting the p27 E3 ligase SCFSkp2 results in p27- and Skp2-mediated cell cycle arrest, and activation of autophagy
Qing Chen, Weilin Xie, Deborah J. Kuhn, Peter M. Voorhees, Antonia Lopez-Girona, Derek Mendy, Laura G. Corral, Veronique Plantevin Krenitsky, Weiming Xu, Laure Moutouh-de Parseval, David R. Webb, Frank Mercurio, Keiichi I. Nakayama, Keiko Nakayama, and Robert Z Orlowski*
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Celgene Signal Research Division, San Diego, CA, United States
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Division of Developmental Genetics, Tohoku University Graduate School of Medicine, Miyagi, Japan
Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
* Corresponding author; email: rorlowsk{at}mdanderson.org.
Decreased p27Kip1 levels are a poor prognostic factor in many malignancies, and can occur through up-regulation of SCFSkp2 E3 ligase function, resulting in enhanced p27 ubiquitination and proteasome-mediated degradation. While proteasome inhibitors stabilize p27Kip1, agents inhibiting SCFSkp2 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 SCFSkp2 ligase function in vitro, and induced specific accumulation of p21 and other SCFSkp2 substrates in cells without activating a heat shock protein response. CpdA prevented incorporation of Skp2 into the SCFSkp2 ligase, and induced G1/S cell cycle arrest as well as SCFSkp2- 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 SCFSkp2 inhibitors as a novel class of anti-tumor agents.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Is exclusive Skp2 targeting always beneficial in cancer therapy?
- Marilena Koutsami, Georgia Velimezi, Athanassios Kotsinas, Konstantinos Evangelou, Athanassios G Papavassiliou, Christos Kittas, and Vassilis G. Gorgoulis
Blood 2008 112: 4777-4779.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
J. J. Fuster, P. Fernandez, H. Gonzalez-Navarro, C. Silvestre, Y. N. Abu Nabah, and V. Andres
Control of cell proliferation in atherosclerosis: insights from animal models and human studies
Cardiovasc Res,
December 3, 2009;
(2009)
cvp363v2.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Hoang, A. Benavides, Y. Shi, P. Frost, and A. Lichtenstein
Effect of autophagy on multiple myeloma cell viability
Mol. Cancer Ther.,
July 1, 2009;
8(7):
1974 - 1984.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Koutsami, G. Velimezi, A. Kotsinas, K. Evangelou, A. G Papavassiliou, C. Kittas, and V. G. Gorgoulis
Is exclusive Skp2 targeting always beneficial in cancer therapy?
Blood,
December 1, 2008;
112(12):
4777 - 4779.
[Full Text]
[PDF]
|
|
|
|
|
