Glutamine metabolism, a double agent combating or fuelling hepatocellular carcinoma

The reprogramming of glutamine metabolism is a key event in cancers in general, and in hepatocellular carcinoma (HCC) in particular. This reprogramming supplies the tumor with ATP and metabolites, through glutamine consumption which is needed for the anaplerosis of the tricarboxylic acid cycle (TCA). Alternatively, glutamine production can be enhanced through an overexpression of the Glutamine Synthetase. In HCC, this specifically occurs through activating mutations in CTNNB1 gene coding β-catenin. Increased glutamine synthesis or use impacts tumor epigenetics, oxidative stress, autophagy, immunity and associated pathways such as mammalian target of rapamycin (mTOR). In this review, we will discuss studies which emphasize the pro-tumoral or tumor suppressive effect of glutamine overproduction. The current state of knowledge highlights the need for more comprehensive studies to evolve suitable targeted therapies which would rely on glutamine metabolic pathways, depending on the predicted pro- or anti-tumor role of the dysregulated glutamine metabolism occurring in distinct genetic contexts.