mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer
Amaia Zabala-Letona,Amaia Arruabarrena-Aristorena,Natalia Martín-Martín,Sonia Fernández-Ruiz,James D. Sutherland,Michelle Clasquin,Julen Tomás-Cortázar,Jose Jimenez,Inés Cristina Torres,Phong Quang,Pilar Ximénez-Embún,Ruzica Bago,Aitziber Ugalde-Olano,Ana Loizaga-Iriarte,Isabel Lacasa-Viscasillas,Miguel Unda,Verónica Torrano,Diana Cabrera,Sebastiaan M. Van Liempd,Ylenia Cendon,Elena 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 Zúñiga-García,Itziar Fernández-Domínguez,Marco Piva,Alfredo Caro-Maldonado,Pilar Sanchez-Mosquera,Mireia Castillo-Martin,Mireia Castillo-Martin,Violeta Serra,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,Juan M. Falcón-Pérez,Rosa Barrio,Teresa Macarulla,Teresa Macarulla,José M. Mato,María L. Martínez-Chantar,Carlos Cordon-Cardo,Ana M. Aransay,Kevin R Marks,José Baselga,Josep Tabernero,Josep Tabernero,Paolo Nuciforo,Brendan D. Manning,Katya Marjon,Arkaitz Carracedo +68 more
TLDR
It is shown that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity.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.read more
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mTOR signalling and cellular metabolism are mutual determinants in cancer.
TL;DR: The interdependencies of mTOR signalling and metabolism pathways in cancer and how metabolic reprogramming in response to changes in m TOR signalling and vice versa can sustain tumorigenicity are discussed.
Journal ArticleDOI
The functions and regulation of the PTEN tumour suppressor: new modes and prospects
TL;DR: New insights are provided into its anti-oncogenic functions and offer novel opportunities for cancer treatment through restoration of PTEN tumour suppressor activity.
Journal ArticleDOI
Polyamine metabolism and cancer: treatments, challenges and opportunities
TL;DR: New insights into molecular mechanisms that link the dysregulation of polyamine metabolism with carcinogenesis and strategies for targeting this pathway for cancer therapy are discussed.
Journal ArticleDOI
Methionine metabolism in health and cancer: a nexus of diet and precision medicine
TL;DR: A link between nutrition and tumour cell metabolism that may allow for tumour-specific metabolic vulnerabilities that can be influenced by diet is established and the potential of targeting methionine metabolism in cancer through dietary or pharmacological intervention is discussed.
Journal ArticleDOI
Molecular logic of mTORC1 signalling as a metabolic rheostat
TL;DR: The authors discuss the molecular logic of the mTORC1 signalling network and its importance in coupling growth signals to the control of cellular metabolism and how to modulate it.
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