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 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...

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Autores: Zabala-Letona, Amaia, Arruabarrena-Aristorena, Amaia|||0000-0002-1636-3944, Martín Martín, Natalia, Fernández Ruiz, Sonia, Sutherland, James D.|||0000-0003-3229-793X, Clasquin, Michelle, Tomás Cortázar, Julen, Jiménez, José, Torres Ramírez, Inés Ma. de, Quang, Phong, Ximénez-Embún, Pilar|||0000-0002-2582-9443, Bago, Ruzica, Ugalde Olano, Aitziber, Loizaga Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Torrano, Verónica, Cabrera, Diana, van Liempd, Sebastiaan M., Cendon, Ylenia, Castro, Elena|||0000-0002-3691-6454, Murray, Stuart, Revandkar, Ajinkya, Alimonti, Andrea, Zhang, Yinan, Barnett, Amelia, Lein, Gina, Pirman, David, Cortazar, Ana Rosa|||0000-0002-7082-5695, Arreal, Leire, Prudkin, Ludmila, Astobiza, Ianire|||0000-0002-7142-7066, Valcarcel-Jimenez, Lorea, Zúñiga-García, Patricia, Fernández Domínguez, Itziar, Piva, Marco, Caro-Maldonado, Alfredo|||0000-0002-5431-7949, Sánchez Mosquera, Pilar, Castillo Martín, Mireia, Serra, Violeta|||0000-0001-6620-1065, Beraza, Naiara, Gentilella, Antonio|||0000-0002-6830-2086, Thomas, George|||0000-0002-1236-1714, Azkargorta, Mikel, Elortza, Felix|||0000-0001-8839-5438, Farràs, Rosa, Olmos, David, Efeyan, Alejo, Anguita, Juan, Muñoz, Javier|||0000-0003-3288-3496, Falcón-Pérez, Juan M.|||0000-0003-3133-0670, Barrio, Rosa|||0000-0002-9663-0669, Macarulla Mercadé, Teresa|||0000-0002-5856-4082, Mato, José M., Martínez Chantar, Maria L., Cordon Cardo, Carlos, Aransay, Ana M.|||0000-0002-8271-612X, Marks, Kevin, Baselga Torres, Josep, Tabernero, Josep|||0000-0002-2495-8139, Nuciforo, Paolo|||0000-0003-1380-0990, Manning, Brendan D., Marjon, Katya, Carracedo, Arkaitz|||0000-0001-5957-1260
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:186284
Acceso en línea:https://ddd.uab.cat/record/186284
https://dx.doi.org/urn:doi:10.1038/nature22964
Access Level:acceso abierto
Descripción
Sumario: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.

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