Zabala Letona, AmaiaArruabarrena-Aristorena, AmaiaMartín Martín, NataliaFernández Ruiz, SoniaSutherland, James DavidClasquin, MichelleTomas Cortazar, JulenJimenez, JoseTorres, Inés deQuang, PhongXiménez Embún, PilarBago, RuzicaUgalde Olano, AitziberLoizaga Iriarte, AnaLacasa-Viscasillas, IsabelUnda Urzaiz, MiguelTorrano, VerónicaCabrera, Dianavan Liempd, Sebastiaan M.Cendon, YleniaCastro, ElenaMurray, StuartRevandkar, AjinkyaAlimonti, AndreaZhang, YinanBarnett, AmeliaLein, GinaPirman, DavidCortazar, Ana RosaArreal, LeirePrudkin, LudmilaAstobiza, IanireValcarcel Jimenez, LoreaZuñiga García, PatriciaFernandez-Dominguez, ItziarPiva, MarcoCaro Maldonado, AlfredoSánchez Mosquera, PilarCastillo Martin, MireiaSerra Elizalde, VioletaBeraza, NaiaraGentilella, AntonioThomas, GeorgeAzkargorta, MikelElortza, FelixFarràs, RosaOlmos, DavidEfeyan, AlejoAnguita, JuanMuñoz, JavierFalcón Pérez, Juan ManuelBarrio, RosaMacarulla, TeresaMato, José M.Martínez Chantar, Maria LuzCordon Cardo, CarlosAransay, Ana M.Marks, KevinBaselga Torres, Josep, 1959-2021Tabernero Caturla, JosepNuciforo, PaoloManning, Brendan D.Marjon, KatyaCarracedo, Arkaitz2020-05-032020-05-032017-07-060028-0836https://hdl.handle.net/2445/158497Activation 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.5 p.application/pdfeng(c) Nature Publishing Group, 2017Proteïnes quinasesCàncer de pròstataProtein kinasesProstate cancerinfo:eu-repo/semantics/article6729852020-05-03info:eu-repo/semantics/openAccess28658205