ABSTRACT
This corrects the article DOI: 10.1038/nature22964.
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.
Subject(s)
Adenosylmethionine Decarboxylase/metabolism , Multiprotein Complexes/metabolism , Polyamines/metabolism , Prostatic Neoplasms/metabolism , TOR Serine-Threonine Kinases/metabolism , Adenosylmethionine Decarboxylase/immunology , Animals , Cell Proliferation , Enzyme Activation , Everolimus/therapeutic use , Humans , Male , Mechanistic Target of Rapamycin Complex 1 , Metabolomics , Mice , Multiprotein Complexes/antagonists & inhibitors , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Protein Stability , S-Adenosylmethionine/analogs & derivatives , S-Adenosylmethionine/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitorsABSTRACT
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.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Energy Metabolism , Liver Neoplasms/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , AMP-Activated Protein Kinase Kinases , Animals , Blotting, Western , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cyclopentanes/pharmacology , Hep G2 Cells , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice, Inbred C57BL , Mice, Knockout , Mice, Nude , NEDD8 Protein , Prohibitins , Protein Processing, Post-Translational/drug effects , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Pyrimidines/pharmacology , RNA Interference , Repressor Proteins/genetics , Repressor Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Signal Transduction/genetics , Transplantation, Heterologous , Ubiquitins/genetics , Ubiquitins/metabolismABSTRACT
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.
