TY - JOUR
T1 - Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence
AU - Lin, Hui Kuan
AU - Chen, Zhenbang
AU - Wang, Guocan
AU - Nardella, Caterina
AU - Lee, Szu Wei
AU - Chan, Chan Hsin
AU - Yang, Wei Lei
AU - Wang, Jing
AU - Egia, Ainara
AU - Nakayama, Keiichi I.
AU - Cordon-Cardo, Carlos
AU - Teruya-Feldstein, Julie
AU - Pandolfi, Pier Paolo
N1 - Funding Information:
Acknowledgements We are grateful to C. J. Sherr, S. W. Lowe and M. Oren for mice and reagents. We would also like to thank B. Carver, L. DiSantis, J. Clossey and S. Megan for editing and critical reading of the manuscript, J. A. Koutcher, C. Le, C. Matei and M. Lupa for MRI analysis, as well all the members of the Pandolfi laboratory for comments and discussion. We extend our thanks to M. Rolfe, P. G. Smith, and Millennium Pharmaceuticals for discussion and for providing the MLN4924 compound. This work was supported by NIH grants to P.P.P. and M.D. Anderson Trust Scholar Award and DOD Prostate Cancer New Investigator Award to H.K.L.
PY - 2010/3/18
Y1 - 2010/3/18
N2 - 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.
AB - 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.
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U2 - 10.1038/nature08815
DO - 10.1038/nature08815
M3 - Article
C2 - 20237562
AN - SCOPUS:77949741498
SN - 0028-0836
VL - 464
SP - 374
EP - 379
JO - Nature
JF - Nature
IS - 7287
ER -