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This corrects the article DOI: 10.1038/nature22964.
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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.
Assuntos
Adenosilmetionina Descarboxilase/metabolismo , Complexos Multiproteicos/metabolismo , Poliaminas/metabolismo , Neoplasias da Próstata/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adenosilmetionina Descarboxilase/imunologia , Animais , Proliferação de Células , Ativação Enzimática , Everolimo/uso terapêutico , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Metabolômica , Camundongos , Complexos Multiproteicos/antagonistas & inibidores , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Estabilidade Proteica , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
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.
Assuntos
Carcinoma Hepatocelular/metabolismo , Metabolismo Energético , Neoplasias Hepáticas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Animais , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Ciclopentanos/farmacologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Proteína NEDD8 , Proibitinas , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Pirimidinas/farmacologia , Interferência de RNA , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transplante Heterólogo , Ubiquitinas/genética , Ubiquitinas/metabolismoRESUMO
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.
