Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer.

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.

• Authors: Lucía Barbier-Torres, Teresa C Delgado, Juan L García-Rodríguez, Imanol Zubiete-Franco, David Fernández-Ramos, Xabier Buqué, Ainara Cano, Virginia Gutiérrez-de Juan, Itziar Fernández-Domínguez, Fernando Lopitz-Otsoa, Pablo Fernández-Tussy, Loreto Boix, Jordi Bruix, Erica Villa, Azucena Castro, Shelly C Lu, Patricia Aspichueta, Dimitris Xirodimas, Marta Varela-Rey, José M Mato, Naiara Beraza, María L Martínez-Chantar
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 4 Pg. 2509-23 (Feb 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25650664 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclopentanes
• NEDD8 Protein
• NEDD8 protein, human
• PHB protein, human
• Prohibitins
• Pyrimidines
• Repressor Proteins
• Ubiquitins
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases
• pevonedistat

Topics

• AMP-Activated Protein Kinase Kinases
• Animals
• Blotting, Western
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cyclopentanes (pharmacology)
• Energy Metabolism
• Hep G2 Cells
• Hepatocytes (drug effects, metabolism)
• Humans
• Liver Neoplasms (genetics, metabolism, pathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Nude
• NEDD8 Protein
• Prohibitins
• Protein Processing, Post-Translational (drug effects)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Pyrimidines (pharmacology)
• RNA Interference
• Repressor Proteins (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects, genetics)
• Transplantation, Heterologous
• Ubiquitins (genetics, metabolism)