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, Pier Paolo Pandolfi

Research output: Contribution to journalArticlepeer-review

310 Citations (Scopus)

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 p19 Arf ĝ€"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.

Original languageEnglish
Pages (from-to)374-379
Number of pages6
JournalNature
Volume464
Issue number7287
DOIs
Publication statusPublished - Mar 18 2010

All Science Journal Classification (ASJC) codes

  • General

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