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...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2017
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/158497
Acceso en línea:https://hdl.handle.net/2445/158497
Access Level:acceso abierto
Palabra clave:Proteïnes quinases
Càncer de pròstata
Protein kinases
Prostate cancer
Descripción
Sumario: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.

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