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Title: mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer
Author: 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
Ximenez Embun, 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, Violeta
Beraza, Naiara
Gentilella, Antonio
Thomas, George
Azkargorta, Mikel
Elortza, Felix
Farràs, Rosa
Olmos, David
Efeyan, Alejo
Anguita, Juan
Muñoz, Javier
Falcón Pérez, Juan M.
Barrio, Rosa
Macarulla, Teresa
Mato, José M.
Martínez Chantar, Maria Luz
Cordon Cardo, Carlos
Aransay, Ana M.
Marks, Kevin
Baselga Torres, Josep, 1959-
Tabernero Caturla, Josep
Nuciforo, Paolo
Manning, Brendan D.
Marjon, Katya
Carracedo, Arkaitz
Keywords: Proteïnes quinases
Càncer de pròstata
Protein kinases
Prostate cancer
Issue Date: 6-Jul-2017
Publisher: Nature Publishing Group
Abstract: 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.
Note: Versió postprint del document publicat a:
It is part of: Nature, 2017, vol. 547, p. 109-113
Related resource:
ISSN: 0028-0836
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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