A recent publication in Cell demonstrates that arginine, an amino acid that facilitates various cellular processes, including cellular growth, also promotes tumor growth. The study shows that arginine reprograms the metabolism of the tumor, a mechanism that many cancer cells use to replicate continuously.
The liver's primary functions include metabolizing nutrients obtained from food and storing energy for later use by the body. Thus, the liver is highly involved in the body's metabolic balance.
Over the past two decades, a growing body of evidence suggests cancer is a metabolic disease. Almost all cancers, regardless of the tissue in which they develop, have an impairment in energy metabolism.
The researchers demonstrate elevated arginine levels in biopsies from patients with liver cancer. The arginine levels remain high despite the same samples containing arginine synthesis genes. The high arginine levels occur, in part, because the cancer cells take in excess arginine from the environment. The study shows that the high arginine levels induce tumor formation and accelerate metabolic reprogramming.
The study focuses on a molecule, RBM39, which plays a role in excessive arginine uptake and subsequent tumor growth. The exciting part of the story comes when the researchers deplete RBM39 using a drug called indisulam. Known as a “molecular glue,” indisulam unites RBM39 and an enzyme known as an E3 ubiquitin ligase resulting in the eventual degradation of RBM39.
Indisulam-driven depletion of RBM39 blocks metabolic reprogramming in liver cancer cells, making it a potential target for therapeutic intervention. Because other cells, including the immune cells needed to fight cancer, require arginine, the authors suggest that possible strategies to control arginine through manipulating RMB39 could alleviate side effects associated with other approaches to broadly limit arginine in circulation.
Further research to evaluate the efficacy of targeting RMB39 to treat liver cancer could identify a new therapeutic approach for treating liver cancer. Importantly, as most cancers involve metabolic reprogramming, successfully identifying such an approach could be applied to additional cancer types.
Sources: Cell, Cancers, Nutrition Metabolism, Nature, Molecular Biomedicine
