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), rend...

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Autores: Alimonti, Andrea, Nardella, Caterina, Chen, Zhenbang, Clohessy, John G., Carracedo, Arkaitz, Trotman, Lloyd C., Cheng, Ke, Varmeh, Shohreh, Kozma, Sara C., Thomas, George, Rosivatz, Erika, Woscholski, Rudiger, Cognetti, Francesco, Scher, Howard I., Pandolfi, Pier Paolo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2010
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/177199
Acceso en línea:https://hdl.handle.net/2445/177199
Access Level:acceso abierto
Palabra clave:Proliferació cel·lular
ADN
Càncer de pròstata
Cell proliferation
DNA
Prostate cancer
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spelling A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesisAlimonti, AndreaNardella, CaterinaChen, ZhenbangClohessy, John G.Carracedo, ArkaitzTrotman, Lloyd C.Cheng, KeVarmeh, ShohrehKozma, Sara C.Thomas, GeorgeRosivatz, ErikaWoscholski, RudigerCognetti, FrancescoScher, Howard I.Pandolfi, Pier PaoloProliferació cel·lularADNCàncer de pròstataCell proliferationDNAProstate cancerIrreversible 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.American Society for Clinical Investigation2010info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/177199Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1172/JCI40535Journal of Clinical Investigation, 2010, vol. 120, num. 3, p. 681-693https://doi.org/10.1172/JCI40535(c) American Society for Clinical Investigation, 2010info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1771992026-05-27T06:46:51Z
dc.title.none.fl_str_mv A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
title A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
spellingShingle A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
Alimonti, Andrea
Proliferació cel·lular
ADN
Càncer de pròstata
Cell proliferation
DNA
Prostate cancer
title_short A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
title_full A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
title_fullStr A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
title_full_unstemmed A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
title_sort A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis
dc.creator.none.fl_str_mv Alimonti, Andrea
Nardella, Caterina
Chen, Zhenbang
Clohessy, John G.
Carracedo, Arkaitz
Trotman, Lloyd C.
Cheng, Ke
Varmeh, Shohreh
Kozma, Sara C.
Thomas, George
Rosivatz, Erika
Woscholski, Rudiger
Cognetti, Francesco
Scher, Howard I.
Pandolfi, Pier Paolo
author Alimonti, Andrea
author_facet Alimonti, Andrea
Nardella, Caterina
Chen, Zhenbang
Clohessy, John G.
Carracedo, Arkaitz
Trotman, Lloyd C.
Cheng, Ke
Varmeh, Shohreh
Kozma, Sara C.
Thomas, George
Rosivatz, Erika
Woscholski, Rudiger
Cognetti, Francesco
Scher, Howard I.
Pandolfi, Pier Paolo
author_role author
author2 Nardella, Caterina
Chen, Zhenbang
Clohessy, John G.
Carracedo, Arkaitz
Trotman, Lloyd C.
Cheng, Ke
Varmeh, Shohreh
Kozma, Sara C.
Thomas, George
Rosivatz, Erika
Woscholski, Rudiger
Cognetti, Francesco
Scher, Howard I.
Pandolfi, Pier Paolo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Proliferació cel·lular
ADN
Càncer de pròstata
Cell proliferation
DNA
Prostate cancer
topic Proliferació cel·lular
ADN
Càncer de pròstata
Cell proliferation
DNA
Prostate cancer
description 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.
publishDate 2010
dc.date.none.fl_str_mv 2010
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/177199
url https://hdl.handle.net/2445/177199
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1172/JCI40535
Journal of Clinical Investigation, 2010, vol. 120, num. 3, p. 681-693
https://doi.org/10.1172/JCI40535
dc.rights.none.fl_str_mv (c) American Society for Clinical Investigation, 2010
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Society for Clinical Investigation, 2010
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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