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2.
Nature ; 547(7661): 109-113, 2017 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-28658205

RESUMEN

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.


Asunto(s)
Adenosilmetionina Descarboxilasa/metabolismo , Complejos Multiproteicos/metabolismo , Poliaminas/metabolismo , Neoplasias de la Próstata/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Adenosilmetionina Descarboxilasa/inmunología , Animales , Proliferación Celular , Activación Enzimática , Everolimus/uso terapéutico , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Metabolómica , Ratones , Complejos Multiproteicos/antagonistas & inhibidores , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Estabilidad Proteica , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores
3.
Oncotarget ; 6(4): 2509-23, 2015 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-25650664

RESUMEN

The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Metabolismo Energético , Neoplasias Hepáticas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Ciclopentanos/farmacología , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Proteína NEDD8 , Prohibitinas , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Pirimidinas/farmacología , Interferencia de ARN , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Trasplante Heterólogo , Ubiquitinas/genética , Ubiquitinas/metabolismo
4.
Ultrasound Med Biol ; 37(7): 1161-9, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21645964

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of hepatic damage in developed countries. For this reason, mouse models of NAFLD have been developed to show progression of the disease because it perfectly resembles the human pathology. Here we show that diagnostic high-frequency ultrasound imaging (US) may be used as an effective method for monitoring the progression of liver disease, from steatosis to hepatocellular carcinoma in the methionine adenosyl transferase and glycine N-methyltransferase-deficient mice models. US reliably detected murine liver lesions associated with NAFLD in the two mice strains tested, with excellent agreement among US images, gross pathology and histological sections. Our results suggest US as a relevant approach for the study of NAFLD in mice, with interesting technical and therapeutic implications.


Asunto(s)
Hígado Graso/diagnóstico por imagen , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hígado Graso/patología , Masculino , Ratones , Ratones Endogámicos , Ultrasonografía
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