Carregant...
Fitxers
Tipus de document
ArticleVersió
Versió publicadaData de publicació
Llicència de publicació
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/120778
Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer
Títol de la revista
Director/Tutor
ISSN de la revista
Títol del volum
Recurs relacionat
Resum
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.
Matèries (anglès)
Citació
Citació
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. Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer. _Oncotarget_. 2014. Vol. 6, núm. 4, pàgs. 2509-2523. [consulta: 20 de gener de 2026]. ISSN: 1949-2553. [Disponible a: https://hdl.handle.net/2445/120778]