Fuente: Biomolecules - Revista científica (MDPI) Biomolecules, Vol. 16, Pages 449: Inhibition of Glutamate Dehydrogenase as a Potential Strategy to Modulate Intrahepatic Cholangiocarcinoma Cell Metabolism
Biomolecules doi: 10.3390/biom16030449
Authors:
Anna Santarsiero
Ilaria Pappalardo
Alessandro Santarsiere
Ernesto Santoro
Marisabel Mecca
Antonio Evidente
Pierluigi Reveglia
Lucia Lecce
Federica De Carlo
Carlo Calabrese
Vittoria Infantino
Stefano Superchi
Simona Todisco

Cholangiocarcinoma (CCA) is a rare malignancy of the biliary tree with increasing global incidence and mortality and limited therapeutic options. Intrahepatic cholangiocarcinoma (iCCA) metabolism exhibits enhanced glycolysis, oxidative phosphorylation, and glutamine utilization. In this study, we investigated the therapeutic potential of targeting glutaminolysis in iCCA, identifying glutamate dehydrogenase (GDH)—which converts glutamate to α-ketoglutarate—as a key metabolic hub. We evaluated the effects of pomegranate waste extract (PWE), a by-product of industrial pomegranate juice production, on cell viability, proliferation, migration, ATP production, and extracellular acidification in CCLP1 cells, an established iCCA model. Our results are consistent with an altered cellular energy metabolism. We further assessed GDH enzymatic activity, expression, and transcriptional regulation in the presence or absence of PWE and its major components, punicalagin and ellagic acid. GDH expression was downregulated by PWE in a dose-dependent manner through inhibition of NF-κB signaling, revealing a new mechanistic link between NF-κB and GDH. In addition, GDH enzymatic activity was dose-dependently inhibited by PWE, as well as punicalagin and ellagic acid. Notably, punicalagin was identified as a novel competitive inhibitor of GDH. Overall, these findings provide the first evidence that modulation of glutaminolysis through GDH targeting impairs iCCA cell growth and metabolism, supporting GDH as a promising metabolic target. This study highlights pomegranate-derived compounds as potential leads for the development of adjunctive or preventive strategies in intrahepatic cholangiocarcinoma.