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http://hdl.handle.net/2445/120778
Title: | Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer |
Author: | Barbier Torres, Lucía Delgado, Teresa C. García Rodríguez, Juan L. Zubiete Franco, Imanol Fernández Ramos, David Buqué, Xabier Cano, Ainara Gutiérrez de Juan, Virginia Fernández Domínguez, Itziar Lopitz Otsoa, Fernando Fernández Tussy, Pablo Boix i Ferrero, Loreto Bruix Tudó, Jordi Villa, Erica Castro, Azucena Lu, Shelly C. Aspichueta, Patricia Xirodimas, Dimitris Varela Rey, Marta Mato, José M. Beraza, Naiara Martínez Chantar, Maria Luz |
Keywords: | Càncer de fetge Metabolisme cel·lular Cèl·lules canceroses Cicle cel·lular Liver cancer Cell metabolism Cancer cells Cell cycle |
Issue Date: | 11-Dec-2014 |
Publisher: | Impact Journals |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.3191 |
It is part of: | Oncotarget, 2014, vol. 6, num. 4, p. 2509-2523 |
URI: | http://hdl.handle.net/2445/120778 |
Related resource: | https://doi.org/10.18632/oncotarget.3191 |
ISSN: | 1949-2553 |
Appears in Collections: | Articles publicats en revistes (Medicina) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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