Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

Abstract

Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro 1-3 , but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer 4,5 . Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription 6-10 . Here we show that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers nonlethal invasive prostate cancer after long latency. Strikingly, combined inactivation of Pten and Trp53 elicits invasive prostate cancer as early as 2 weeks after puberty and is invariably lethal by 7 months of age. Importantly, acute Pten inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which can be fully rescued by combined loss of Trp53. Furthermore, we detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Our results demonstrate the relevance of cellular senescence in restricting tumorigenesis in vivo and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of Pten-deficient tumours.'Cellular senescence' describes a permanent form of cell cycle arrest in primary cultured cells, which can be triggered by DNA damage or activated oncogenes 1-3 . Although it has been implicated in mediating the response to anti-tumour treatments 11 , there is still no evidence that senescence opposes tumorigenesis.Up to 70% of primary prostate tumours lose one PTEN allele and retain the other copy 12-15 . Similarly, p53 is found completely lost or mutated almost exclusively in advanced prostate cancer 16,17 . Because complete loss of Pten in the mouse seems to be crucial for the development of invasive prostate tumours 18,19 , why human invasive prostate cancer wouldCorrespondence and requests for materials should be addressed to P.P.P. (p-pandolfi@ski.mskcc.org). Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.Supplementary Information is linked to the online version of the paper at www.nature.com/nature. (Supplementary Fig. S1). As expected, in the presence of Pb-Cre4, recombination of Pten and Trp53 was restricted to the three prostatic lobes, namely the anterior prostate (AP), ventral prostate (VP) and dorsolateral prostate (DLP), with minor recombination occurring in seminal vesicles ( Supplementary Fig. S2a). NIH Public AccessTo study early effects of Pten and/or Trp53 inactivation in the prostate, mice were killed at 9 weeks of age and histopathological analysis was performed. Wild-type (WT) mice displayed normal prostate histology, whereas age-matched Pten pc−/− littermate...

JunB and PTEN in prostate cancer: ‘loss is nothing else than change’

“…Previous studies showed that PTEN induces the activation of a p53-dependent cellular senescence response. 13 In the present study, Thomsen et al observed increased cellular proliferation after the loss of both Pten and JunB and decreased expression of the cell cycle inhibitors p16 Ink4a and p21 CIP1 , which are key inducers of cellular senescence (Figure 1). 14 These findings were supported by data from three different gene expression data sets of human PCa samples, were low-grade tumors express JUNB, but high-grade and metastatic tumors are devoid of JUNB and p21 CIP expression.…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Like apoptosis, senescence has been proposed as a tumor suppressor mechanism (Braig et al, 2005;Chen et al, 2005;Collado et al, 2005;Lazzerini Denchi et al, 2005;Michaloglou et al, 2005). In normal cells, genotoxic and oncogenic stress activate the p53-p21 and p16-pRB pathways, respectively, leading to transient or permanent growth arrest.…”

Androgen receptor and prostate cancer

“…33 Akt activation is inhibited by the tumor suppressor gene PTEN, suggesting that loss of PTEN, a frequent abnormAndrogen receptor and prostate cancer E Richter et al ality detected in advanced prostate cancer, may lead to progression to androgen independence in CaP. [34][35][36][37] …”