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

Abstract

Cellular senescence has been recently shown to play an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or loss of tumour suppressor genes is thought to critically dependent on the 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, tumor-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic stress driven senescence neither elicits activation of the p19Arf-p53 pathway nor DNA damage, but instead depends 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 Skp2 pharmacological inhibition may represent a general approach for cancer prevention and therapy.

Repression of cancer cell senescence by PKCι

“…This occurred in the absence of any detectable increase in cell death, as assessed by flow cytometry. Cultures of MCF7 and T47D cells depleted of PKCi also showed a decrease in the percentage of cells incorporating 5-bromodeoxyuridine (BrdU), consistent with decreased cell division causing the decrease in viable cell numbers observed (Figure 3c DNA damage (either telomeric in the case of replicative senescence or non-telomeric in the case of premature senescence) is a common, although not universally observed (Denoyelle et al, 2006;Lin et al, 2010), feature of senescence and DNA-damage responses have an important role in the initiation and maintenance of the senescent phenotype . To assay whether DNA-damage response pathways were activated upon PKCi depletion in breast cancer cells, the presence of gH2AX foci was assessed by immunofluorescence microscopy.…”

“…We did not see any evidence for activation of the DNA-damage response with PKCi depletion in either breast cancer or glioblastoma cells. Other groups have also described senescence that occurs in the absence of detectable DNA-damage response pathway activation (Denoyelle et al, 2006;Lin et al, 2010). The lack of a requirement for p53 and p16, along with the absence of activation of a DNA-damage response, suggests a novel mechanism for senescence induction upon PKCi depletion.…”

“…A recent paper has described senescence activation in the absence of DNA damage in mice that have cell-cycle defects owing to loss of Skp2 expression (Lin et al, 2010). Mice that are hypomorphic for the spindle checkpoint kinase Bub1 also show enhanced senescence (Baker et al, 2004).…”

“…Previous data have linked impaired mitosis to senescence activation (Baker et al, 2004;Lin et al, 2010), and our recent data have indicated a role for PKCi in mitosis (Baldwin et al, 2010). As an alternate means to impairing mitosis, the effects of aurora kinase inhibition on senescence were assessed, both in the absence and presence of PKCi depletion.…”

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

“…Nevertheless, a growing body of evidence supports the involvement of other pathways in the regulation of senescence, and in particular, in that of oncogene‐induced senescence (OIS) (Bianchi‐Smiraglia & Nikiforov, 2012; Christoffersen et al., 2010; Cipriano et al., 2011; Humbert et al., 2010; Lin et al., 2010; Scurr et al., 2010). …”