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oai:repisalud.isciii.es:20.500.12105/173232024-09-27T12:00:14Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927col_20.500.12105_16962col_20.500.12105_16968col_20.500.12105_16983
Repisalud author Zabala-Letona, Amaia author Arruabarrena-Aristorena, Amaia author Martín-Martín, Natalia author Fernandez-Ruiz, Sonia author Sutherland, James D author Clasquin, Michelle author Tomas-Cortazar, Julen author Jimenez, Jose author Torres, Ines author Quang, Phong author Ximenez-Embun, Pilar author Bago, Ruzica author Ugalde-Olano, Aitziber author Loizaga-Iriarte, Ana author Lacasa-Viscasillas, Isabel author Unda, Miguel author Torrano, Verónica author Cabrera, Diana author van Liempd, Sebastiaan M author Cendon, Ylenia author Castro, Elena author Murray, Stuart author Revandkar, Ajinkya author Alimonti, Andrea author Zhang, Yinan author Barnett, Amelia author Lein, Gina author Pirman, David author Cortazar, Ana R author Arreal, Leire author Prudkin, Ludmila author Astobiza, Ianire author Valcarcel-Jimenez, Lorea author Zuñiga-García, Patricia author Fernandez-Dominguez, Itziar author Piva, Marco author Caro-Maldonado, Alfredo author Sánchez-Mosquera, Pilar author Castillo-Martín, Mireia author Serra, Violeta author Beraza, Naiara author Gentilella, Antonio author Thomas, George author Azkargorta, Mikel author Elortza, Felix author Farràs, Rosa author Olmos, David author Efeyan, Alejo author Anguita, Juan author Muñoz, Javier author Falcón-Pérez, Juan M author Barrio, Rosa author Macarulla, Teresa author Mato, Jose M author Martinez-Chantar, Maria L author Cordon-Cardo, Carlos author Aransay, Ana M author Marks, Kevin author Baselga, José author Tabernero, Josep author Nuciforo, Paolo author Manning, Brendan D author Marjon, Katya author Carracedo, Arkaitz 2024-01-23T20:12:56Z 2024-01-23T20:12:56Z 2017-06-28 10.1038/nature22964 1476-4687 Nature http://hdl.handle.net/10668/11354 28658205 http://hdl.handle.net/20.500.12105/17323 Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. 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 model and human biopsies 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 everolimus 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. eng mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. research article