A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
Andrea Alimonti, … , Howard I. Scher, Pier Paolo Pandolfi
Andrea Alimonti, … , Howard I. Scher, Pier Paolo Pandolfi
Published February 8, 2010
Citation Information: J Clin Invest. 2010;120(3):681-693. https://doi.org/10.1172/JCI40535.
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Research Article Oncology

A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis

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.

Authors

Andrea Alimonti, Caterina Nardella, Zhenbang Chen, John G. Clohessy, Arkaitz Carracedo, Lloyd C. Trotman, Ke Cheng, Shohreh Varmeh, Sara C. Kozma, George Thomas, Erika Rosivatz, Rudiger Woscholski, Francesco Cognetti, Howard I. Scher, Pier Paolo Pandolfi

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Figure 4

mTOR is essential for senescence upon Pten loss.

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mTOR is essential for senescence upon Pten loss. (A) Western blot analys...
(A) Western blot analysis of primary Ptenlx/lx MEFs after rapamycin treatment and acute inactivation of Pten with Ad-Cre (PtenΔ/Δ), according to the experimental scheme shown in Supplemental Figure 1E. Numbers indicate densitometrically determined protein levels relative to β-actin. Senescence-associated β-gal staining and its quantification is also shown. Scale bar: 10 μm. Error bars show SD. (B) Western analysis in Pten-deficient and Pten-mTOR compound mutant primary MEFs (by retroviral infection/selection). Numbers indicate densitometrically determined protein levels for p53 relative to β-actin. Senescence-associated β-gal staining and its quantification is also shown. Scale bar: 10 μm. Error bars show SD. (C) Western analysis of Pten–/–p19Arf–/– compound mutant MEFs (by retroviral infection/selection) and quantification of p53 levels. Error bars show SD of 3 independent experiments. (D) MEFs as in C, treated with rapamycin (rapa) or DMSO for 24 hours. Error bars show SD of 3 independent experiments. (E) Western blot analysis and quantification for Pten and p53 protein levels of MEFs infected as in A and treated with MG132 48 hours after infection. Error bars show SD of 3 independent experiments. (C–E) Numbers within and above columns indicate the average p53 levels observed in independent experiments. (F) Senescence-associated β-gal staining and quantification of PtenΔ/Δ MEFs treated with rapamycin and/or Nutlin-3 during Ad-Cre–mediated PICS. Scale bar: 10 μm. Error bars show SD of 3 independent experiments. P indicates the statistical significance as measured by Student’s t test throughout.