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.
View: Text | PDF
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

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

×

Figure 1

Senescence driven by Pten loss occurs in the absence of cellular proliferation.

Options: View larger image (or click on image) Download as PowerPoint
Senescence driven by Pten loss occurs in the absence of cellular prolife...
(A) Western blot analysis of Ptenlx/lx MEFs infected with Ad-GFP or Ad-Cre, according to the scheme in Supplemental Figure 1E. β-gal staining for senescence and its quantification. Scale bar: 10 μm. Growth curve of Ptenlx/lx MEFs after infection with Ad-GFP or Ad-Cre. (B) Quantification of β-gal staining for senescence and Western blot analysis for p53 in Ptenlx/lx MEFs treated according to the experimental timeline. The asterisk denotes analysis through either Western blotting or β-gal staining. Images show β-gal staining for senescence (at 24 hours). Scale bar: 10 μm. (C) Quantification of BrdU incorporation in Ptenlx/lx MEFs infected as in B. (D) Analysis of cellular proliferation and Western blot analysis for p53 of Ptenlx/lx primary MEFs infected with retroviral control vector, H-Ras (OIS), and Cre (PICS), as measured by relative cell number over a 6-day period, and followed without selection. Note that the absence of selection was required, since H-Ras induced hyperproliferation 2 days after the infection of MEFs (a shorter time point than that observed in human cell lines; ref. 18), and the selection phase masked this phenomenon. Experimental design for the experiment is shown in the lower panel. (E) Quantification of β-gal staining and Western blot analysis for p53 at day 6 for Ptenlx/lx primary MEFs infected as in D (see experimental design in D). Numbers in the Western blots indicate densitometrically determined protein levels relative to β-actin (A, B, D, and E). Error bars show SD (A–E).