A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
Open Access
- 1 March 2010
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 120 (3), 681-693
- https://doi.org/10.1172/jci40535
Abstract
Irreversible cell growth arrest, a process termed cellular senescence, is emerging as an intrinsic tumor suppressive mechanism. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment. We previously demonstrated in a mouse model of prostate cancer that inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (Pten) elicits a senescence response that opposes tumorigenesis. Here, we show that Pten-loss–induced cellular senescence (PICS) represents a senescence response that is distinct from oncogene-induced senescence and can be targeted for cancer therapy. Using mouse embryonic fibroblasts, we determined that PICS occurs rapidly after Pten inactivation, in the absence of cellular proliferation and DDR. Further, we found that PICS is associated with enhanced p53 translation. Consistent with these data, we showed that in mice p53-stabilizing drugs potentiated PICS and its tumor suppressive potential. Importantly, we demonstrated that pharmacological inhibition of PTEN drives senescence and inhibits tumorigenesis in vivo in a human xenograft model of prostate cancer. Taken together, our data identify a type of cellular senescence that can be triggered in nonproliferating cells in the absence of DNA damage, which we believe will be useful for developing a “pro-senescence” approach for cancer prevention and therapy.Keywords
This publication has 46 references indexed in Scilit:
- Survival signalling by Akt and eIF4E in oncogenesis and cancer therapyNature, 2004
- In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2Science, 2004
- A PCR primer bank for quantitative gene expression analysisNucleic Acids Research, 2003
- Pten Dose Dictates Cancer Progression in the ProstatePLoS Biology, 2003
- Tumor cell senescence in cancer treatment.2003
- Isolation of Polysomal RNA for Microarray AnalysisMethods in molecular biology (Clifton, N.J.), 2002
- p21 modulates threshold of apoptosis induced by DNA-damage and growth factor withdrawal in prostate cancer cellsCarcinogenesis: Integrative Cancer Research, 2002
- An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity inPten+/−miceProceedings of the National Academy of Sciences of the United States of America, 2001
- Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTORProceedings of the National Academy of Sciences of the United States of America, 2001
- Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouseNature Genetics, 2001