2026-04-17T06:18:49Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1207782025-12-04T19:11:21Zcom_2072_1057col_2072_478858col_2072_478917col_2072_478921

00925njm 22002777a 4500 dc Barbier Torres, Lucía author Delgado, Teresa C. author García Rodríguez, Juan L. author Zubiete Franco, Imanol author Fernández Ramos, David author Buqué, Xabier author Cano, Ainara author Gutiérrez de Juan, Virginia author Fernández Domínguez, Itziar author Lopitz Otsoa, Fernando author Fernández Tussy, Pablo author Boix i Ferrero, Loreto author Bruix Tudó, Jordi author Villa, Erica author Castro, Azucena author Lu, Shelly C. author Aspichueta, Patricia author Xirodimas, Dimitris author Varela Rey, Marta author Mato, José M. author Beraza, Naiara author Martínez Chantar, Maria Luz author 2018-03-15T15:15:40Z 2018-03-15T15:15:40Z 2014-12-11 2018-03-15T15:15:41Z 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. Càncer de fetge Metabolisme cel·lular Cèl·lules canceroses Cicle cel·lular Liver cancer Cell metabolism Cancer cells Cell cycle Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer