Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/17323
Title
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.
Author(s)
Zabala-Letona, Amaia | Arruabarrena-Aristorena, Amaia | Martín-Martín, Natalia | Fernandez-Ruiz, Sonia | Sutherland, James D | Clasquin, Michelle | Tomas-Cortazar, Julen | Jimenez, Jose | Torres, Ines | Quang, Phong | Ximenez-Embun, Pilar CNIO | Bago, Ruzica | Ugalde-Olano, Aitziber | Loizaga-Iriarte, Ana | Lacasa-Viscasillas, Isabel | Unda, Miguel | Torrano, Verónica | Cabrera, Diana | van Liempd, Sebastiaan M | Cendon, Ylenia | Castro, Elena CNIO | Murray, Stuart | Revandkar, Ajinkya | Alimonti, Andrea | Zhang, Yinan | Barnett, Amelia | Lein, Gina | Pirman, David | Cortazar, Ana R | Arreal, Leire | Prudkin, Ludmila | Astobiza, Ianire | Valcarcel-Jimenez, Lorea | Zuñiga-García, Patricia | Fernandez-Dominguez, Itziar | Piva, Marco | Caro-Maldonado, Alfredo | Sánchez-Mosquera, Pilar | Castillo-Martín, Mireia | Serra, Violeta | Beraza, Naiara | Gentilella, Antonio | Thomas, George | Azkargorta, Mikel | Elortza, Felix | Farràs, Rosa | Olmos, David CNIO | Efeyan, Alejo CNIO | Anguita, Juan | Muñoz, Javier | Falcón-Pérez, Juan M | Barrio, Rosa | Macarulla, Teresa | Mato, Jose M | Martinez-Chantar, Maria L | Cordon-Cardo, Carlos | Aransay, Ana M | Marks, Kevin | Baselga, José | Tabernero, Josep | Nuciforo, Paolo | Manning, Brendan D | Marjon, Katya | Carracedo, Arkaitz
Date issued
2017-06-28
Language
Inglés
Document type
research article
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.
MESH
Adenosylmethionine Decarboxylase | Animals | Cell Proliferation | Enzyme Activation | Everolimus | Humans | Male | Mechanistic Target of Rapamycin Complex 1 | Metabolomics | Mice | Multiprotein Complexes | PTEN Phosphohydrolase | Phosphatidylinositol 3-Kinases | Polyamines | Prostatic Neoplasms | Protein Stability | S-Adenosylmethionine | TOR Serine-Threonine Kinases
DOI
Collections
- Investigación > IIS > IMIM - Hospital del Mar Research Institute-Barcelona (Cataluña)
- Investigación > IIS > IBIMA-Plataforma BIONAND - Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (Andalucía)
- Investigación > IIS > IDIBELL - Instituto de Investigación Biomédica de Bellvitge (Cataluña)
- Investigación > IIS > IdiSNA - Instituto de Investigación Sanitaria de Navarra (Navarra)
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