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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We thank N. Sonenberg for providing 4EBP1- and 4EBP2-targeting shRNAs, D. Alessi for discussions and technical advice, A.M. Cuervo and E. Arias-Perez for technical advice, the Basque biobank for research (BIOEF) for critical support with human specimens and Novartis for providing SAM486A. Funding: Ramón y Cajal award (to A.C., A.E., J.M., D.O.), Juan de la Cierva (to E.C., A.C.-M.), BFU grant (to R.B.: BFU2014-52282-P and BFU2011-25986), SAF grant (to A.C.: SAF2016-79381-R, FEDER/EU; M.L.M.-C.: SAF2014-54658-R; to J.M.F.-P.: SAF2015-66312; to J.M.M: SAF 2014-52097R; to A.E.: SAF2015-67538-R; to J.A.: SAF2015-65327R; to G.T.: SAF2011-24967) from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO); European Union (to A.C.: ERC-StG-336343, PoC754627; to A.C.-M.: CIG 660191; to J.A.: 602272; to A.E.: ERC-2014-STG-638891); Basque Government Department of Health (to V.T.: 2016111109; to J.M.F.-P: 2015111149), Department of Education (to A.C.: PI2012/03 and IKERTALDE I.T.1106-16; to R.B.: PI2012/42; to M.L.M.-C.: 2013) and PhD grants (to A.A.-A. and L.V.-J.); AECC (to V.T.: 2016 JP Bizkaia; to N.M.-M.: 2011 JP Bizkaia; to M.L.M.-C.); ISCIII (to A.C.: PI10/01484, PI13/00031; to J.M.: Proteored PR.B.2 and grant PT13/0001; to R.F.: PI15/209; to V.S.: PI13/01714, CP14/00228); Ramón Areces foundation (to J.M.F.-P.); Basque Department of Industry, Tourism and Trade (Etortek) (to A.C.); FERO Foundation (to A.C., V.S.); Fundación Vasca de Innovación e Investigación Sanitarias, BIOEF (to V.T.: BIO15/CA/052); BBVA Foundation (to A.C.; P.N. team); National Institutes of Health (to C.C.-C. and M.C.: P01CA087497; to J.M.M.: R01AT001576); Fundación CRIS contra el Cáncer (to D.O. team); 2014 Stewart Rahr Young Investigator Award from the Prostate Cancer Foundation (to D.O.); FPU predoctoral fellowship (to Y.C.: 15/05126); Catalan Agency AGAUR (to V.S.: 2014 SGR 1331); Medical Research Council (to R. Bago, D. Alessi laboratory: grant number MC_UU_12016/2). The activity of CIBERONC was co-funded with FEDER funds.
Extended data figures
Complete list of detected ions in the Time-of-flight analysis.
Candidate pathways extracted from TOF-MS analysis.
Pathway enrichment analysis of the 73 ions consistently altered in the mouse model analysis.
Clinicopathological characteristics of patients with prostate pathology. pN, Lymph node positivity; Pn, Perineural invasion.
Relevant mass isotopomer values in the 13C-U5-Methionine administration analysis by LC/MS.
Effect of SAM486A administration (5mg/Kg; 5 days/week) in immunocompetent C57BL/6 mice.
LC/MS analysis in prostate tissue extracts from WT and TRAMP (TRAMP+/T) mice.
Clinic-pathological characteristics of patients enrolled in the Everolimus clinical trial.