A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
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
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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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 5

Nutlin-3 potentiates senescence and acts synergistically to RAD001 in restricting tumorigenesis in vivo.

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Nutlin-3 potentiates senescence and acts synergistically to RAD001 in re...
(A) Schematic representation of the timing of drug administration in the different treatment groups (n = 10 for each group). sac, sacrifice. (B) Sizes of the anterior prostate in Ptenpc–/– mice (8 weeks of age) after the indicated treatments. (C) Quantification of the anterior prostates (APs) size and number of PIN-affected glands in mice (n = 6 for each treatment group) treated with the indicated drugs. Error bars show SD. P indicates the statistical significance (untreated versus each group of treatments). (D) Histopathological analysis and senescence of 8-week-old prostate tumors after treatments and staining as indicated: H&E, pS6, β-gal, p53, and Ki-67. Insets in H&E, pS6, p53, and Ki-67 represent a WT control stained as indicated (original magnification, ×20). (E) Quantification of the β-gal staining in anterior prostate sections of mice treated as indicate Representative sections from 3 mice were counted for each treatment group. Sections were counterstained with DAPI staining for β-gal quantification. (F) Quantification of p53 in the anterior prostate sections of mice treated as indicated. Sections from 3 mice were counted for each treatment group. (G) Quantification of Ki-67 staining in anterior prostates of mice treated as indicated and quantified as in E. (H) Quantification of TUNEL assay for apoptosis in the anterior prostates of mice treated as indicated (more than 3 mice per treatment group). Error bars in E–H represent SD for a representative experiment performed in triplicate. (I) Summary of the molecular pathway and pharmacological manipulation of PI3K pathway for pro-senescence therapy for cancer.