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

Nature. 2010 Mar 18;464(7287):374-9. doi: 10.1038/nature08815.

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)-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 p19(Arf)-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 p19(Arf)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Adenovirus E1A Proteins / genetics
  • Adenovirus E1A Proteins / metabolism
  • Animals
  • Cell Transformation, Neoplastic* / drug effects
  • Cells, Cultured
  • Cellular Senescence* / drug effects
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Fibroblasts
  • Male
  • Mice
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Prostate / cytology
  • Prostate / metabolism
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / prevention & control
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • S-Phase Kinase-Associated Proteins / antagonists & inhibitors
  • S-Phase Kinase-Associated Proteins / genetics
  • S-Phase Kinase-Associated Proteins / metabolism*
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Adenovirus E1A Proteins
  • Atf4 protein, mouse
  • Cdkn1b protein, mouse
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • S-Phase Kinase-Associated Proteins
  • Tumor Suppressor Protein p53
  • Activating Transcription Factor 4
  • Cyclin-Dependent Kinase Inhibitor p27
  • SKP Cullin F-Box Protein Ligases
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Proto-Oncogene Proteins p21(ras)