Prognostic and Functional Role of the Glutamine Metabolism in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy. Therapeutic options are limited for this aggressive tumor type due to a lack of druggable drivers, resulting in a poor 5-year survival. One particular feature of cancer cells is the metabolic reprogramming of glutaminolysis, which contributes to energy and macromolecule homeostasis of several tumor types, including iCCA. YAP/TAZ, members of the Hippo pathway ubiquitously activated in iCCA, can coordinate glutaminolysis modulating metabolic enzymes such as glutaminase (GLS1). Herein, we investigated the expression levels of glutaminolysis members SLC1A5, SLC7A5, SLC38A1, and GLS1 in human iCCA specimens dependent on the YAP/TAZ status utilizing Real-time PCR, immunoblotting, immunohistochemistry, and a Glutamine/Glutamate assay. The cytotoxic effect of the selective SLC1A5 competitor V-9302 and the GLS1 inhibitor Telaglenastat, alone or combined, was determined on HuCCT1, KKU213, and RBE iCCA cell lines, and the correlation of glutamine pathway members and YAP/TAZ expression in murine iCCA models overexpressing AKT/YAP or AKT/TAZ. In sum, we found significantly augmented expression levels of SLC1A5, SLC7A5, SLC38A1, and GLS1, as well as YAP/TAZ in human and mouse iCCA specimens. SLC1A5, SLC7A5, YAP, and TAZ expression was inversely correlated with patient’s prognosis. Knockdown of YAP/TAZ in iCCA cell lines led to decreased SLC1A5, SLC7A5, and SLC38A1 levels, and diminished glutamate production. Both inhibitors demonstrated anti-proliferative activity, with V-9302 being the most effective, also synergizing with the anti-mitochondrial drug Devimistat in vitro and in ovo. The present data indicate that glutaminolysis is a negative prognostic factor and a potential actionable target in iCCA.

Publication History

Article published online:
23 January 2024