mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer
Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation1,2. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrati...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2017 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/158497 |
| Acesso em linha: | https://hdl.handle.net/2445/158497 |
| Access Level: | acceso abierto |
| Palavra-chave: | Proteïnes quinases Càncer de pròstata Protein kinases Prostate cancer |
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mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancerZabala Letona, AmaiaArruabarrena-Aristorena, AmaiaMartín Martín, NataliaFernández Ruiz, SoniaSutherland, James DavidClasquin, MichelleTomas Cortazar, JulenJimenez, JoseTorres, Inés deQuang, PhongXiménez Embún, PilarBago, RuzicaUgalde Olano, AitziberLoizaga Iriarte, AnaLacasa-Viscasillas, IsabelUnda Urzaiz, MiguelTorrano, VerónicaCabrera, Dianavan Liempd, Sebastiaan M.Cendon, YleniaCastro, ElenaMurray, StuartRevandkar, AjinkyaAlimonti, AndreaZhang, YinanBarnett, AmeliaLein, GinaPirman, DavidCortazar, Ana RosaArreal, LeirePrudkin, LudmilaAstobiza, IanireValcarcel Jimenez, LoreaZuñiga García, PatriciaFernandez-Dominguez, ItziarPiva, MarcoCaro Maldonado, AlfredoSánchez Mosquera, PilarCastillo Martin, MireiaSerra Elizalde, VioletaBeraza, NaiaraGentilella, AntonioThomas, GeorgeAzkargorta, MikelElortza, FelixFarràs, RosaOlmos, DavidEfeyan, AlejoAnguita, JuanMuñoz, JavierFalcón Pérez, Juan ManuelBarrio, RosaMacarulla, TeresaMato, José M.Martínez Chantar, Maria LuzCordon Cardo, CarlosAransay, Ana M.Marks, KevinBaselga Torres, Josep, 1959-2021Tabernero Caturla, JosepNuciforo, PaoloManning, Brendan D.Marjon, KatyaCarracedo, ArkaitzProteïnes quinasesCàncer de pròstataProtein kinasesProstate cancerActivation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation1,2. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model3 and human biopsies4 of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus5 exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.Nature Publishing Group2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/158497Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1038/nature22964Nature, 2017, vol. 547, p. 109-113https://doi.org/10.1038/nature22964info:eu-repo/grantAgreement/EC/H2020/660191info:eu-repo/grantAgreement/EC/FP7/602272info:eu-repo/grantAgreement/EC/H2020/754627info:eu-repo/grantAgreement/EC/H2020/638891info:eu-repo/grantAgreement/EC/H2020/683136info:eu-repo/grantAgreement/EC/FP7/336343(c) Nature Publishing Group, 2017info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1584972026-05-27T06:46:51Z |
| dc.title.none.fl_str_mv |
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer |
| title |
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer |
| spellingShingle |
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer Zabala Letona, Amaia Proteïnes quinases Càncer de pròstata Protein kinases Prostate cancer |
| title_short |
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer |
| title_full |
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer |
| title_fullStr |
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer |
| title_full_unstemmed |
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer |
| title_sort |
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer |
| dc.creator.none.fl_str_mv |
Zabala Letona, Amaia Arruabarrena-Aristorena, Amaia Martín Martín, Natalia Fernández Ruiz, Sonia Sutherland, James David Clasquin, Michelle Tomas Cortazar, Julen Jimenez, Jose Torres, Inés de Quang, Phong Ximénez Embún, Pilar Bago, Ruzica Ugalde Olano, Aitziber Loizaga Iriarte, Ana Lacasa-Viscasillas, Isabel Unda Urzaiz, Miguel Torrano, Verónica Cabrera, Diana van Liempd, Sebastiaan M. Cendon, Ylenia Castro, Elena Murray, Stuart Revandkar, Ajinkya Alimonti, Andrea Zhang, Yinan Barnett, Amelia Lein, Gina Pirman, David Cortazar, Ana Rosa Arreal, Leire Prudkin, Ludmila Astobiza, Ianire Valcarcel Jimenez, Lorea Zuñiga García, Patricia Fernandez-Dominguez, Itziar Piva, Marco Caro Maldonado, Alfredo Sánchez Mosquera, Pilar Castillo Martin, Mireia Serra Elizalde, Violeta Beraza, Naiara Gentilella, Antonio Thomas, George Azkargorta, Mikel Elortza, Felix Farràs, Rosa Olmos, David Efeyan, Alejo Anguita, Juan Muñoz, Javier Falcón Pérez, Juan Manuel Barrio, Rosa Macarulla, Teresa Mato, José M. Martínez Chantar, Maria Luz Cordon Cardo, Carlos Aransay, Ana M. Marks, Kevin Baselga Torres, Josep, 1959-2021 Tabernero Caturla, Josep Nuciforo, Paolo Manning, Brendan D. Marjon, Katya Carracedo, Arkaitz |
| author |
Zabala Letona, Amaia |
| author_facet |
Zabala Letona, Amaia Arruabarrena-Aristorena, Amaia Martín Martín, Natalia Fernández Ruiz, Sonia Sutherland, James David Clasquin, Michelle Tomas Cortazar, Julen Jimenez, Jose Torres, Inés de Quang, Phong Ximénez Embún, Pilar Bago, Ruzica Ugalde Olano, Aitziber Loizaga Iriarte, Ana Lacasa-Viscasillas, Isabel Unda Urzaiz, Miguel Torrano, Verónica Cabrera, Diana van Liempd, Sebastiaan M. Cendon, Ylenia Castro, Elena Murray, Stuart Revandkar, Ajinkya Alimonti, Andrea Zhang, Yinan Barnett, Amelia Lein, Gina Pirman, David Cortazar, Ana Rosa Arreal, Leire Prudkin, Ludmila Astobiza, Ianire Valcarcel Jimenez, Lorea Zuñiga García, Patricia Fernandez-Dominguez, Itziar Piva, Marco Caro Maldonado, Alfredo Sánchez Mosquera, Pilar Castillo Martin, Mireia Serra Elizalde, Violeta Beraza, Naiara Gentilella, Antonio Thomas, George Azkargorta, Mikel Elortza, Felix Farràs, Rosa Olmos, David Efeyan, Alejo Anguita, Juan Muñoz, Javier Falcón Pérez, Juan Manuel Barrio, Rosa Macarulla, Teresa Mato, José M. Martínez Chantar, Maria Luz Cordon Cardo, Carlos Aransay, Ana M. Marks, Kevin Baselga Torres, Josep, 1959-2021 Tabernero Caturla, Josep Nuciforo, Paolo Manning, Brendan D. Marjon, Katya Carracedo, Arkaitz |
| author_role |
author |
| author2 |
Arruabarrena-Aristorena, Amaia Martín Martín, Natalia Fernández Ruiz, Sonia Sutherland, James David Clasquin, Michelle Tomas Cortazar, Julen Jimenez, Jose Torres, Inés de Quang, Phong Ximénez Embún, Pilar Bago, Ruzica Ugalde Olano, Aitziber Loizaga Iriarte, Ana Lacasa-Viscasillas, Isabel Unda Urzaiz, Miguel Torrano, Verónica Cabrera, Diana van Liempd, Sebastiaan M. Cendon, Ylenia Castro, Elena Murray, Stuart Revandkar, Ajinkya Alimonti, Andrea Zhang, Yinan Barnett, Amelia Lein, Gina Pirman, David Cortazar, Ana Rosa Arreal, Leire Prudkin, Ludmila Astobiza, Ianire Valcarcel Jimenez, Lorea Zuñiga García, Patricia Fernandez-Dominguez, Itziar Piva, Marco Caro Maldonado, Alfredo Sánchez Mosquera, Pilar Castillo Martin, Mireia Serra Elizalde, Violeta Beraza, Naiara Gentilella, Antonio Thomas, George Azkargorta, Mikel Elortza, Felix Farràs, Rosa Olmos, David Efeyan, Alejo Anguita, Juan Muñoz, Javier Falcón Pérez, Juan Manuel Barrio, Rosa Macarulla, Teresa Mato, José M. Martínez Chantar, Maria Luz Cordon Cardo, Carlos Aransay, Ana M. Marks, Kevin Baselga Torres, Josep, 1959-2021 Tabernero Caturla, Josep Nuciforo, Paolo Manning, Brendan D. Marjon, Katya Carracedo, Arkaitz |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Proteïnes quinases Càncer de pròstata Protein kinases Prostate cancer |
| topic |
Proteïnes quinases Càncer de pròstata Protein kinases Prostate cancer |
| description |
Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation1,2. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model3 and human biopsies4 of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus5 exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program. |
| publishDate |
2017 |
| dc.date.none.fl_str_mv |
2017 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion |
| format |
article |
| status_str |
acceptedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/158497 |
| url |
https://hdl.handle.net/2445/158497 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Versió postprint del document publicat a: https://doi.org/10.1038/nature22964 Nature, 2017, vol. 547, p. 109-113 https://doi.org/10.1038/nature22964 info:eu-repo/grantAgreement/EC/H2020/660191 info:eu-repo/grantAgreement/EC/FP7/602272 info:eu-repo/grantAgreement/EC/H2020/754627 info:eu-repo/grantAgreement/EC/H2020/638891 info:eu-repo/grantAgreement/EC/H2020/683136 info:eu-repo/grantAgreement/EC/FP7/336343 |
| dc.rights.none.fl_str_mv |
(c) Nature Publishing Group, 2017 info:eu-repo/semantics/openAccess |
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(c) Nature Publishing Group, 2017 |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
Nature Publishing Group |
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Nature Publishing Group |
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Articles publicats en revistes (Ciències Fisiològiques) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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1869410256698736640 |
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15,300719 |