mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.

Détails

ID Serval
serval:BIB_A2A21769118A
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.
Périodique
Nature
Auteur(s)
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., Cendon Y., Castro E., Murray S., Revandkar A., Alimonti A., Zhang Y., Barnett A., Lein G., Pirman D., Cortazar A.R., Arreal L., Prudkin L., Astobiza I., Valcarcel-Jimenez L., Zuñiga-García P., Fernandez-Dominguez I., Piva M., Caro-Maldonado A., Sánchez-Mosquera P., Castillo-Martín M., Serra V., Beraza N., Gentilella A., Thomas G., Azkargorta M., Elortza F., Farràs R., Olmos D., Efeyan A., Anguita J., Muñoz J., Falcón-Pérez J.M., Barrio R., Macarulla T., Mato J.M., Martinez-Chantar M.L., Cordon-Cardo C., Aransay A.M., Marks K., Baselga J., Tabernero J., Nuciforo P., Manning B.D., Marjon K., Carracedo A.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Statut éditorial
Publié
Date de publication
06/07/2017
Peer-reviewed
Oui
Volume
547
Numéro
7661
Pages
109-113
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.

Mots-clé
Adenosylmethionine Decarboxylase/immunology, Adenosylmethionine Decarboxylase/metabolism, Animals, Cell Proliferation, Enzyme Activation, Everolimus/therapeutic use, Humans, Male, Metabolomics, Mice, Multiprotein Complexes/antagonists & inhibitors, Multiprotein Complexes/metabolism, PTEN Phosphohydrolase/metabolism, Phosphatidylinositol 3-Kinases/metabolism, Polyamines/metabolism, Prostatic Neoplasms/drug therapy, Prostatic Neoplasms/metabolism, Prostatic Neoplasms/pathology, Protein Stability, S-Adenosylmethionine/analogs & derivatives, S-Adenosylmethionine/metabolism, TOR Serine-Threonine Kinases/antagonists & inhibitors, TOR Serine-Threonine Kinases/metabolism
Pubmed
Web of science
Création de la notice
04/09/2017 18:39
Dernière modification de la notice
20/08/2019 15:08
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