2015/02/17

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

Liver Cancer, the fifth most common cancer worldwide and the third leading cause of death, is a very complex and heterogeneous pathology with multiple and distinct signaling pathways that converge in the same malignant transformation. The laboratory of María Luz Martínez Chantar in the Metabolomics Unit at CIC bioGUNE has identified the effect of the post-translational modification NEDDylation in the signaling and metabolism of liver cancer and its potential as a new therapeutic approach. NEDD8 expression is markedly increased in poor survival patients with hepatocellular carcinoma. The stabilization of two oncokinases, Akt and LKB1, that are hallmarks of proliferative metabolism in tumoral cells was shown to be dependent on NEDDylation in liver cancer. The susceptibility to NEDD8-dependent apoptotic stimuli was found to be modulated through the regulation of the levels of these proteins opening a new scenery for a personalized HCC treatment.

Importantly, the NEDDylation inhibition achieved through the experimental drug MLN4924 (Millennium) in liver cancer animal models, correlates with a tumor regression and a strong modulation in the cancer metabolomics signature.

These results reveal for the first time a completely new and unexplored role of NEDD8 in the stabilization of crucial proteins that are involved in HCC development, emphasizing the general feature of NEDDylation in cancer.

This study was recently published in the journal "Oncotarget".
Barbier Torres L, Delgado TC et al.