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 3

Pharmacological inhibition of PTEN drives senescence in vitro and in vivo.

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Pharmacological inhibition of PTEN drives senescence in vitro and in viv...
(A) Quantification of the senescence-associated β-gal assay and its staining in Pten+/+ (WT) and Pten+/– (HET) cells treated with indicated concentrations of the PTEN inhibitor VO-OHpic. Scale bar: 10 μm. Error bars show SD. (B) Western analysis of cells from A treated with 500 nM VO-OHpic. Blot lanes were run on the same gel but were noncontiguous. (C) Quantification of pAkt (Ser 473)/Akt protein levels in Pten+/+ and Pten+/– MEFs from A, normalized for the WT baseline level (dashed line). Error bars show SD from independent experiments. (D) Quantification of senescence-associated β-gal staining in Pten-null MEFs treated with either vehicle or 500 nM VO-OHpic. Error bars show SD. (E) Western analysis for PTEN and its quantification in 6 prostate cancer cell lines with WT (black bars) and mutant (red bars) p53. Error bars show SD from independent experiments. (F) Fold increase in tumor volume in a MDA PCa 2b xenograft mouse model after systemic treatment with VO-OHpic. Error bars show SD. A representative Western blot analysis for p53 in tumors from mice treated with Vehicle or VO-OHpic is shown in the inset. Numbers in the inset indicate densitometrically determined protein levels for p53 relative to β-actin (G) Quantification of β-gal– and Ki-67–positive cells in MDA PCa 2b tumors, untreated and treated with VO-OHpic. Error bars show SD. P indicates the statistical significance as measured by Student’s t test throughout.