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MTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.

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.

SUBMITTER: Zabala-Letona A

PROVIDER: S-EPMC5505479 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

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

Nature 20170628 7661

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. ...[more]

PMID: 28658205

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Project description:Curcumin, a natural polyphenol that contributes to the flavor and yellow pigment of the spice turmeric, is known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin has potential utility for both chemoprevention and chemotherapy. Previous studies demonstrated that curcumin can inhibit ornithine decarboxylase (ODC) activity in human leukemia and breast cancer cells, and pretreatment with dietary curcumin blocks carcinogen-induced ODC activity in rodent models of skin, colon, and renal cancer. The current study investigated the regulation of polyamine metabolism in human gastric and colon carcinoma cell lines in response to curcumin. Curcumin treatment significantly induced spermine oxidase (SMOX) mRNA and activity, which results in the generation of hydrogen peroxide, a source of ROS. Simultaneously, curcumin down regulated spermidine/spermine N1-acetyltransferase (SSAT) activity and the biosynthetic enzymes ODC and S-adenosylmethionine decarboxylase (SAMDC), thereby diminishing intracellular polyamine pools. Combination treatments using curcumin with the ODC inhibitor 2-difluoromethylornithine (DFMO), an agent currently in clinical chemoprevention trials, significantly enhanced inhibition of ODC activity and decreased growth of GI cancer cell lines beyond that observed with either agent alone. Similarly, combining curcumin with the polyamine analogue bis(ethyl)norspermine enhanced growth inhibition that was accompanied by enhanced accumulation of the analogue and decreased intracellular polyamine levels beyond those observed with either agent alone. Importantly, cotreatment with curcumin permitted the lowering of the effective dose of ODC inhibitor or polyamine analogue. These studies provide insight into the polyamine-related mechanisms involved in the cancer cell response to curcumin and its potential as a chemopreventive or chemotherapeutic agent in the GI tract.

Dataset Information

MTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.

Publications

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

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