The Pleiotropic Effects of Glutamine Metabolism in Cancer

Abstract

Metabolic programs are known to be altered in cancers arising from various tissues. Malignant transformation can alter signaling pathways related to metabolism and increase the demand for both energy and biomass for the proliferating cancerous cells. This scenario is further complexed by the crosstalk between transformed cells and the microenvironment. One of the most common metabolic alterations, which occurs in many tissues and in the context of multiple oncogenic drivers, is the increased demand for the amino acid glutamine. Many studies have attributed this increased demand for glutamine to the carbon backbone and its role in the tricarboxylic acid (TCA) cycle anaplerosis. However, an increasing number of studies are now emphasizing the importance of glutamine functioning as a proteogenic building block, a nitrogen donor and carrier, an exchanger for import of other amino acids, and a signaling molecule. Herein, we highlight the recent literature on glutamine's versatile role in cancer, with a focus on nitrogen metabolism, and therapeutic implications of glutamine metabolism in cancer.

Keywords: cancer; glutamate; glutamate ammonia ligase (GLUL); glutaminase (GLS); glutamine; glutamine synthetase (GS); glutaminolysis; metabolism.

Figure 1

While glutamine can be converted to glutamate to exert functions indicated on the left-hand side, glutamine has its own specific functions: (1) The terminal amide group in glutamine (highlighted in orange) is the primary nitrogen source for several macromolecules; (2) the entire glutamine molecule can function to drive the uptake of essential amino acids (EAA) and activate mTOR; (3) the glutamine synthesis reaction can help balance pH and detoxify ammonia and glutamate.

Figure 2

Glutamine metabolism in tumor microenvironment. Tumor cells can obtain glutamine via macropinocytosis of extracellular proteins, or via the import of free glutamine secreted by cancer-associated fibroblasts (CAFs) or adipocytes [47,92]. Tumor cells communicate with CAFs via instructional miRNAs in exosomal vesicles (EVs) and secrets glutamate and ammonia as wastes that can be taken up by CAFs for glutamine synthesis [93]. In a cell autonomous manner, a decrease in glutamine synthetase activity in tumor-associated macrophages (TAMs) can reprogram glucose and glutamine metabolism and lead to polarizing cells from an M2 to M1-like phenotype which inhibits metastasis [43].