Letter | Published:

mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Nature volume 547, pages 109113 (06 July 2017) | Download Citation

  • A Corrigendum to this article was published on 17 January 2018

This article has been updated

Abstract

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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Change history

  • 17 January 2018

    Please see accompanying Corrigendum (http://doi.org/10.1038/nature25470). In Extended Data Figs 5e and 9h, the protein ‘NSIN1’ was corrected to ‘SIN1’. In Extended Data Fig. 8e, the extracted ion chromatogram of the TVLASPQKIEGFK peptide for phosphorylated AMD1 was added to the left panel, and the following text was added to the figure legend for Extended Data Fig. 8e: “Extracted ion chromatogram (XIC) of the TVLASPQKIEGFK peptide (left);”. In addition, the following affiliation was added to author Violeta Serra: ‘CIBERONC, Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029 Madrid, Spain’.

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Acknowledgements

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.

Author information

Author notes

    • Naiara Beraza

    Present address: Gut Health and Food Safety Programme, Institute of Food Research, Norwich Research Park, Norwich NR4 7UA, UK.

    • Amaia Zabala-Letona
    •  & Amaia Arruabarrena-Aristorena

    These authors contributed equally to this work.

Affiliations

  1. CIC bioGUNE, Bizkaia Technology Park, 801 Building, 48160 Derio, Spain

    • Amaia Zabala-Letona
    • , Amaia Arruabarrena-Aristorena
    • , Natalia Martín-Martín
    • , Sonia Fernandez-Ruiz
    • , James D. Sutherland
    • , Julen Tomas-Cortazar
    • , Verónica Torrano
    • , Diana Cabrera
    • , Sebastiaan M. van Liempd
    • , Ana R. Cortazar
    • , Leire Arreal
    • , Ianire Astobiza
    • , Lorea Valcarcel-Jimenez
    • , Patricia Zuñiga-García
    • , Itziar Fernandez-Dominguez
    • , Marco Piva
    • , Alfredo Caro-Maldonado
    • , Pilar Sánchez-Mosquera
    • , Naiara Beraza
    • , Mikel Azkargorta
    • , Felix Elortza
    • , Juan Anguita
    • , Juan M. Falcón-Pérez
    • , Rosa Barrio
    • , Jose M. Mato
    • , Maria L. Martinez-Chantar
    • , Ana M. Aransay
    •  & Arkaitz Carracedo
  2. CIBERONC, Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029 Madrid, Spain

    • Amaia Zabala-Letona
    • , Natalia Martín-Martín
    • , Sonia Fernandez-Ruiz
    • , Verónica Torrano
    • , Violeta Serra
    • , David Olmos
    • , Teresa Macarulla
    • , Josep Tabernero
    •  & Arkaitz Carracedo
  3. AGIOS Pharmaceuticals, Cambridge, Massachusetts, 02139, USA.

    • Michelle Clasquin
    • , Phong Quang
    • , Stuart Murray
    • , Amelia Barnett
    • , Gina Lein
    • , David Pirman
    • , Kevin Marks
    •  & Katya Marjon
  4. Vall d’Hebron Institute of Oncology (VHIO), Universidad Autónoma de Barcelona, 08035 Barcelona, Spain

    • Jose Jimenez
    • , Ludmila Prudkin
    • , Violeta Serra
    • , Teresa Macarulla
    • , Josep Tabernero
    •  & Paolo Nuciforo
  5. Department of Pathology, Valld’Hebron Hospital, Universitat Autónoma de Barcelona, 08035 Barcelona, Spain

    • Ines Torres
  6. Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain

    • Pilar Ximenez-Embun
    • , Ylenia Cendon
    • , Elena Castro
    • , David Olmos
    • , Alejo Efeyan
    •  & Javier Muñoz
  7. MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK

    • Ruzica Bago
  8. Department of Pathology, Basurto University Hospital, 48013 Bilbao, Spain

    • Aitziber Ugalde-Olano
  9. Department of Urology, Basurto University Hospital, 48013 Bilbao, Spain

    • Ana Loizaga-Iriarte
    • , Isabel Lacasa-Viscasillas
    •  & Miguel Unda
  10. School of Medicine, Universidad Autónoma de Madrid, 28049 Madrid, Spain

    • Ylenia Cendon
  11. Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland

    • Ajinkya Revandkar
    •  & Andrea Alimonti
  12. Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland

    • Ajinkya Revandkar
    •  & Andrea Alimonti
  13. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA

    • Yinan Zhang
    •  & Brendan D. Manning
  14. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York 10029-5674, USA

    • Mireia Castillo-Martín
    •  & Carlos Cordon-Cardo
  15. Department of Pathology, Fundação Champalimaud, 1400-038 Lisboa, Portugal

    • Mireia Castillo-Martín
  16. Laboratory of Metabolism and Cancer, Catalan Institute of Oncology, ICO, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain

    • Antonio Gentilella
    •  & George Thomas
  17. Department of Biochemistry and Physiology, Faculty of Pharmacy, Universitat de Barcelona, 08028 Barcelona, Catalunya, Spain

    • Antonio Gentilella
  18. Carlos III Networked Proteomics Platform (ProteoRed-ISCIII), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029 Madrid, Spain

    • Mikel Azkargorta
    • , Felix Elortza
    •  & Javier Muñoz
  19. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029 Madrid, Spain

    • Felix Elortza
    • , Juan M. Falcón-Pérez
    • , Jose M. Mato
    • , Maria L. Martinez-Chantar
    •  & Ana M. Aransay
  20. Centro de Investigación Príncipe Felipe, Eduardo Primo Yúfera 3, 46012 Valencia, Spain

    • Rosa Farràs
  21. CNIO-IBIMA Genitourinary Cancer Unit, Medical Oncology Department, Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, 29010 Málaga, Spain

  22. Ikerbasque, Basque foundation for science, 48011 Bilbao, Spain

    • Juan Anguita
    • , Juan M. Falcón-Pérez
    •  & Arkaitz Carracedo
  23. Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York 10065, USA

    • José Baselga
  24. Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), 48940 Bilbao, Spain

    • Arkaitz Carracedo

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Contributions

In vitro studies: A.Z.-L. and A.A.-A. with support from N.M.-M., S.F.-R., and L.A. In vivo studies: A.Z.-L., A.A.-A. and N.M.-M. with support for tail vein from N.B. Genotyping: P.S.-M. Metabolomics analysis: M.Clas., P.Q., S.M., A.B., G.L., and D.P., K. Marks and K. Marjon at AGIOS and D.C., S.M.V.L., and J.M.F.-P. at CIC bioGUNE. Everolimus trial samples and staining: V.S., J.J., L.P., P.N., I.T., J.T., T.M., and J.B. Human prostate specimens: A.U.-O., A.L.-I., I.L.-V., and M.U. Histochemical analysis in mice: S.F.-R., A. Rev., and A. Alim. Generation of molecular AMD1 tools: J.D.S. and R.B. Immune cell analysis and GST–AMD1 purification: J.T.-C., I.F.-D., and J.A. Phosphoproteomics: P.X.-E., A.E., and J.M. Kinase assay: R. Bago. TRAMP mice material: statistical supervision and bioinformatics, A.R.-C.; polysome profiling, A.G. and G.T. Genetically engineered mouse model pathology: M.C.-M. and C.C.-C. Technical support and discussions: B.D.M., J.M.M., M.L.M.-C., M.A., F.E., I.A., A.M.A., V.T., L.V.-J., P.Z.-G., M.P., A.C.-M., R.F., and Y.Z. K. Marjon directed the metabolomics strategy, analysed the results, and contributed to discussions and manuscript preparation and revision. A.C. directed the project, supervised data analysis, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Arkaitz Carracedo.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains the uncropped blots.

Excel files

  1. 1.

    Supplementary Table 1

    Complete list of detected ions in the Time-of-flight analysis.

  2. 2.

    Supplementary Table 2

    Candidate pathways extracted from TOF-MS analysis.

  3. 3.

    Supplementary Table 3

    Pathway enrichment analysis of the 73 ions consistently altered in the mouse model analysis.

  4. 4.

    Supplementary Table 4

    Clinicopathological characteristics of patients with prostate pathology. pN, Lymph node positivity; Pn, Perineural invasion.

  5. 5.

    Supplementary Table 5

    Relevant mass isotopomer values in the 13C-U5-Methionine administration analysis by LC/MS.

  6. 6.

    Supplementary Table 6

    Effect of SAM486A administration (5mg/Kg; 5 days/week) in immunocompetent C57BL/6 mice.

  7. 7.

    Supplementary Table 7

    LC/MS analysis in prostate tissue extracts from WT and TRAMP (TRAMP+/T) mice.

  8. 8.

    Supplementary Table 8

    Clinic-pathological characteristics of patients enrolled in the Everolimus clinical trial.

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DOI

https://doi.org/10.1038/nature22964

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