mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer
Zabala-Letona, Amaia (Centro de Investigación Biomédica en Red de Cáncer)
Arruabarrena-Aristorena, Amaia (CIC bioGUNE)
Martín Martín, Natalia (Centro de Investigación Biomédica en Red de Cáncer)
Fernández Ruiz, Sonia (Centro de Investigación Biomédica en Red de Cáncer)
Sutherland, James D. (CIC bioGUNE)
Clasquin, Michelle (AGIOS Pharmaceuticals)
Tomás Cortázar, Julen (CIC bioGUNE)
Jiménez, José (Hospital Universitari Vall d'Hebron)
Torres Ramírez, Inés Ma. de (Hospital Universitari Vall d'Hebron)
Quang, Phong (AGIOS Pharmaceuticals)
Ximénez-Embún, Pilar (Centro Nacional de Investigaciones Oncológicas)
Bago, Ruzica (MRC Protein Phosphorylation and Ubiquitylation Unit)
Ugalde Olano, Aitziber (Hospital de Basurto (Bilbao, Biscaia))
Loizaga Iriarte, Ana (Hospital de Basurto (Bilbao, Biscaia))
Lacasa Viscasillas, Isabel (Hospital de Basurto (Bilbao, Biscaia))
Unda, Miguel (Hospital de Basurto (Bilbao, Biscaia))
Torrano, Verónica (Centro de Investigación Biomédica en Red de Cáncer)
Cabrera, Diana (CIC bioGUNE)
van Liempd, Sebastiaan M. (CIC bioGUNE)
Cendon, Ylenia (Universidad Autónoma de Madrid)
Castro, Elena (Centro Nacional de Investigaciones Oncológicas)
Murray, Stuart (AGIOS Pharmaceuticals)
Revandkar, Ajinkya (University of Lausanne)
Alimonti, Andrea (University of Lausanne)
Zhang, Yinan (Harvard School of Public Health)
Barnett, Amelia (AGIOS Pharmaceuticals)
Lein, Gina (AGIOS Pharmaceuticals)
Pirman, David (AGIOS Pharmaceuticals)
Cortazar, Ana Rosa (CIC bioGUNE)
Arreal, Leire (CIC bioGUNE)
Prudkin, Ludmila (Hospital Universitari Vall d'Hebron)
Astobiza, Ianire (CIC bioGUNE)
Valcárcel Jiménez, Lorea (CIC bioGUNE)
Zúñiga-García, Patricia (CIC bioGUNE)
Fernández Domínguez, Itziar (CIC bioGUNE)
Piva, Marco (CIC bioGUNE)
Caro-Maldonado, Alfredo (CIC bioGUNE)
Sánchez Mosquera, Pilar (CIC bioGUNE)
Castillo Martín, Mireia (Fundação Champalimaud)
Serra, Violeta (Hospital Universitari Vall d'Hebron)
Beraza, Naiara (CIC bioGUNE)
Gentilella, Antonio (Institut Català d'Oncologia)
Thomas, George (Institut Català d'Oncologia)
Azkargorta, Mikel (Carlos III Networked Proteomics Platform)
Elortza, Felix (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Farràs, Rosa (Centro de Investigación Príncipe Felipe (València))
Olmos, David (Hospital Universitario Virgen de la Victoria (Màlaga, Andalusia))
Efeyan, Alejo (Centro Nacional de Investigaciones Oncológicas)
Anguita, Juan (Ikerbasque)
Muñoz, Javier (Carlos III Networked Proteomics Platform)
Falcón Pérez, Juan M. (Ikerbasque)
Barrio, Rosa (CIC bioGUNE)
Macarulla Mercadé, Teresa (Hospital Universitari Vall d'Hebron)
Mato, José M. (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Martínez Chantar, Maria L. (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Cordon Cardo, Carlos (Icahn School of Medicine at Mount Sinai)
Aransay, Ana M. (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Marks, Kevin (AGIOS Pharmaceuticals)
Baselga Torres, Josep, 1959-2021, (Memorial Sloan Kettering Cancer Center)
Tabernero, Josep (Hospital Universitari Vall d'Hebron)
Nuciforo, Paolo (Hospital Universitari Vall d'Hebron)
Manning, Brendan D. (Harvard School of Public Health)
Marjon, Katya (AGIOS Pharmaceuticals)
Carracedo, Arkaitz (University of the Basque Country)
Universitat Autònoma de Barcelona

Data:	2017
Resum:	Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation,. Here we show that mTORC1 regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. Through the use of integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identified alterations in tumours impacting on 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 was validated in murine and human cancer specimens. AMD1 was upregulated in prostate cancer specimens with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibited a predominant decrease in AMD1 immunoreactivity that was associated to 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.
Ajuts:	Ministerio de Economía y Competitividad BFU2014-52282-P Ministerio de Economía y Competitividad BFU2011-25986 Ministerio de Economía y Competitividad SAF2016-79381-R Ministerio de Economía y Competitividad SAF2014-54658-R Ministerio de Economía y Competitividad SAF2015-66312 Ministerio de Economía y Competitividad SAF2014-52097-R Ministerio de Economía y Competitividad SAF2015-67538-R Ministerio de Economía y Competitividad SAF2015-65327-R Ministerio de Economía y Competitividad SAF2011-24967 European Commission 336343 European Commission 754627 European Commission 660191 European Commission 602272 European Commission 638891 Instituto de Salud Carlos III PI10/01484 Instituto de Salud Carlos III PI13/00031 Instituto de Salud Carlos III PT13/0001 Instituto de Salud Carlos III PI15/209 Instituto de Salud Carlos III PI13/01714 Instituto de Salud Carlos III CP14/00228 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1331
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Drets:	Tots els drets reservats.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Nature, Vol. 547 (July 2017) , p. 109-113, ISSN 1476-4687

DOI: 10.1038/nature22964
PMID: 28658205

39 p, 4.7 MB

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