Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence

Hui-Kuan Lin, Zhenbang Chen, Guocan Wang, Caterina Nardella, Szu-Wei Lee, Chan-Hsin Chan, Wei-Lei Yang, Jing Wang, Ainara Egia, Keiichi I. Nakayama, Carlos Cordon-Cardo, Julie Teruya-Feldstein and Pier Paolo Pandolfi ()
Additional contact information
Hui-Kuan Lin: Cancer Biology and Genetics Program,
Zhenbang Chen: Cancer Biology and Genetics Program,
Guocan Wang: Cancer Biology and Genetics Program,
Caterina Nardella: Cancer Biology and Genetics Program,
Szu-Wei Lee: The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
Chan-Hsin Chan: The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
Wei-Lei Yang: The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
Jing Wang: The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
Ainara Egia: Cancer Genetics Program, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA
Keiichi I. Nakayama: Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
Carlos Cordon-Cardo: Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
Julie Teruya-Feldstein: Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
Pier Paolo Pandolfi: Cancer Biology and Genetics Program,

Nature, 2010, vol. 464, issue 7287, 374-379

Abstract: Abstract Cellular senescence has been recently shown to have an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or by loss of tumour suppressor genes is thought to critically depend on induction of the p19Arf–p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumour-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic-stress-driven senescence neither elicit activation of the p19Arf–p53 pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19Arf–p53 response is impaired, whereas a Skp2–SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof-of-principle evidence that pharmacological inhibition of Skp2 may represent a general approach for cancer prevention and therapy.

Date: 2010
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DOI: 10.1038/nature08815

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