mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Amaia Zabala-Letona, Amaia Arruabarrena-Aristorena, Natalia Martín-Martín, Sonia Fernandez-Ruiz, James D Sutherland, Michelle Clasquin, Julen Tomas-Cortazar, Jose Jimenez, Ines Torres, Phong Quang, Pilar Ximenez-Embun, Ruzica Bago, Aitziber Ugalde-Olano, Ana Loizaga-Iriarte, Isabel Lacasa-Viscasillas, Miguel Unda, Verónica Torrano, Diana Cabrera, Sebastiaan M van Liempd, Ylenia CendonElena Polentinos-Castro, Stuart Murray, Ajinkya Revandkar, Andrea Alimonti, Yinan Zhang, Amelia Barnett, Gina Lein, David Pirman, Ana R Cortazar, Leire Arreal, Ludmila Prudkin, Ianire Astobiza, Lorea Valcarcel-Jimenez, Patricia Zuñiga-García, Itziar Fernandez-Dominguez, Marco Piva, Alfredo Caro-Maldonado, Pilar Sánchez-Mosquera, Mireia Castillo-Martín, Violeta Serra, Naiara Beraza, Antonio Gentilella, George Thomas, Mikel Azkargorta, Felix Elortza, Rosa Farràs, David Olmos, Alejo Efeyan, Juan Anguita, Javier Muñoz, Juan M Falcón-Pérez, Rosa Barrio, Teresa Macarulla, Jose M Mato, Maria L Martinez-Chantar, Carlos Cordon-Cardo, Ana M Aransay, Kevin Marks, José Baselga, Josep Tabernero, Paolo Nuciforo, Brendan D Manning, Katya Marjon, Arkaitz Carracedo

Research output: Contribution to journalLetter

50 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)109-113
Number of pages22
JournalNature
Volume547
Issue number7661
Early online date28 Jun 2017
DOIs
Publication statusPublished - 6 Jul 2017

Keywords

  • Journal article

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    Zabala-Letona, A., Arruabarrena-Aristorena, A., Martín-Martín, N., Fernandez-Ruiz, S., Sutherland, J. D., Clasquin, M., Tomas-Cortazar, J., Jimenez, J., Torres, I., Quang, P., Ximenez-Embun, P., Bago, R., Ugalde-Olano, A., Loizaga-Iriarte, A., Lacasa-Viscasillas, I., Unda, M., Torrano, V., Cabrera, D., van Liempd, S. M., ... Carracedo, A. (2017). mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature, 547(7661), 109-113. https://doi.org/10.1038/nature22964