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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 Article has an altmetric score of 23

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

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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 2

Senescence driven by Pten loss occurs in the absence of DNA damage.

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Senescence driven by Pten loss occurs in the absence of DNA damage.
   
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(A) Immunofluorescence staining and its quantification to detect SDF in primary Ptenlx/lx MEFs undergoing Cre (PICS) and H-Ras infection (OIS). Representative images of phospho-ATM (pATM), γ-H2AX, and phospho-p53 (Ser15) (pp53S15) staining. MEFs treated with doxorubicin (DOXO) and UV were used as controls as indicated. (B) Representative images of γ-H2AX and phospho-p53 DNA damaged foci in MEFs treated as in A. Scale bar: 5 μm. (C) Western analysis for DDR markers in UV-treated primary WT MEFs, proliferating primary MEFs (vector), or MEFs undergoing PICS. Numbers in Western blots indicate protein levels for pCHK1, pCHK2, and γ-H2AX relative to β-actin. (D) Western analysis for substrates phosphorylated by ATM/ATR (phospho-S/TQ, PS/TQ) in UV-treated, control, and PICS. (E) TUNEL analysis in proliferating MEFs or MEFs undergoing PICS. WT MEFs treated with doxorubicin were used as a control. (F) Quantification of β-gal staining (at day 6) in Ptenlx/lx MEFs infected as in A and treated with the ARM/ATR inhibitor CGK737 after infection. (G) Quantification of β-gal staining in MEFs infected as in A and transfected with either a control (siCO) or ATM-specific siRNA (siAtm). Western-blot analysis for ATM in MEFs infected and treated as indicated. (H) β-gal and phospho–γ-H2AX staining and its quantification in prostates from 8-week-old Ptenpc–/– mice with prostatic intraepithelial neoplasia. The graph shows γ-H2AX staining in a positive control (a Ptenpc–/– mouse with invasive carcinoma). P values were determined by Student’s t test. Error bars show SD (A and F–H). Original magnification, ×10 (A and E); ×200 (inset in H).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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