A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis.
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.
Alimonti
Andrea
A
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nardella
Caterina
C
Chen
Zhenbang
Z
Clohessy
John G
JG
Carracedo
Arkaitz
A
Trotman
Lloyd C
LC
Cheng
Ke
K
Varmeh
Shohreh
S
Kozma
Sara C
SC
Thomas
George
G
Rosivatz
Erika
E
Woscholski
Rudiger
R
Cognetti
Francesco
F
Scher
Howard I
HI
Pandolfi
Pier Paolo
PP
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D004249:DNA Damage / Q000235:genetics; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D014176:Protein Biosynthesis / Q000235:genetics; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human