Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer
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Lucía Barbier-Torres1, Teresa C. Delgado1, Juan L. García-Rodríguez1, Imanol Zubiete-Franco1, David Fernández-Ramos1, Xabier Buqué2, Ainara Cano3, Virginia Gutiérrez-de Juan1, Itziar Fernández-Domínguez1, Fernando Lopitz-Otsoa1, Pablo Fernández-Tussy1, Loreto Boix4,5, Jordi Bruix4,5, Erica Villa6, Azucena Castro3, Shelly C. Lu7, Patricia Aspichueta2, Dimitris Xirodimas8, Marta Varela-Rey1, José M. Mato1, Naiara Beraza1 and María L. Martínez-Chantar1
1 CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain
2 Department of Physiology, University of the Basque Country UPV/EHU, Faculty of Medicine and Dentistry, Leioa, Bizkaia, Spain
3 OWL, Bizkaia Science and Technology Park, Derio, Bizkaia, Spain
4 Barcelona-Clínic Liver Cancer Group, Institut d’Investigacions Biomèdiques August Pi I Sunyer, Liver Unit, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
5 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
6 Department of Gastroenterology, Azienda Ospedaliero-Universitaria & University of Modena and Reggio Emilia, Modena, Italy
7 Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USC Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, CA, USA
8 Centre de Recherche de Biochimie Macromoléculaire, Montpellier, France
María L. Martínez-Chantar, email:
Keywords: Neddylation; Cancer metabolism; Hepatocellular Carcinoma; LKB1; Akt
Received: September 26, 2014 Accepted: December 10, 2014 Published: December 11, 2014
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.
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