Glutamine Synthetase: Localization Dictates Outcome

Abstract

Glutamine synthetase (GS) is the adenosine triphosphate (ATP)-dependent enzyme that catalyses the synthesis of glutamine by condensing ammonium to glutamate. In the circulatory system, glutamine carries ammonia from muscle and brain to the kidney and liver. In brain reduction of GS activity has been suggested as a mechanism mediating neurotoxicity in neurodegenerative disorders. In cancer, the delicate balance between glutamine synthesis and catabolism is a critical event. In vitro evidence, confirmed in vivo in some cases, suggests that reduced GS activity in cancer cells associates with a more invasive and aggressive phenotype. However, GS is known to be highly expressed in cells of the tumor microenvironment, such as fibroblasts, adipocytes and immune cells, and their ability to synthesize glutamine is responsible for the acquisition of protumoral phenotypes. This has opened a new window into the complex scenario of the tumor microenvironment, in which the balance of glutamine consumption versus glutamine synthesis influences cellular function. Since GS expression responds to glutamine starvation, a lower glutamine synthesizing power due to the absence of GS in cancer cells might apply a metabolic pressure on stromal cells. This event might push stroma towards a GS-high/protumoral phenotype. When referred to stromal cells, GS expression might acquire a 'bad' significance to the point that GS inhibition might be considered a conceivable strategy against cancer metastasis.

Keywords: M2 macrophages; adipocytes; brain; cancer; glutaminase; glutamine; glutamine synthetase; immunometabolism; immunosuppressive; metabolism.

Figure 1

Role of glutamine synthetase (GS) in brain physiology. Brain relies on the reaction catalyzed by GS, which is known to take place mainly in astrocytes, as a fundamental mechanism for ammonia and glutamate removal. Microglia also express GS and participate with astrocytes in this task. Microglia possess an endogenous mechanism modulating their response to a proinflammatory agent, such as lipopolysaccharides (LPSs). By expressing GS microglial response to LPS is controlled, limiting thus the consequent harmful effects on surrounding cells (left). When this mechanism is lost (GS blockade, oxidation-related GS loss of function, GS inhibition with methionine sulfoximine, MSO) microglia engage a strong inflammatory response to LPS, producing inflammatory mediators and effectors, and leading to neuronal damage. ROS: reactive oxygen species; KO: knock-out; IL-12: interleukin-12; IL-6: interleukin-6; IL-1β: interleukin-1β; PGE2: Prostaglandin E2; TNF-α: tumor necrosis factor-alpha; TLR-4: Toll-like receptor 4.

Figure 2

GS expression in cancer versus tumor microenvironment (TME) cells. Reduced ability to synthesize GS, displayed by some cancer cells, might significantly modify the composition of the extracellular milieu in terms of nutrients availability (such as glutamine). Based on the evidence that starvation increases GS levels (by means of forkhead box O3 (FOXO3A) and post-translational protein stabilization), glutamine depletion induced by glutamine dependent-cancer cells might trigger GS expression in cancer associated fibroblasts (CAFs), macrophages, adipocytes and T cells. In these cells glutamine synthesis is known to mediate a metabolic and functional reprogramming. In this way, the inability to synthesize glutamine (reduced GS expression) displayed by some cancer cells might be one of the elements capable of inducing a metabolic pressure on the TME, eventually reprogramming CAFs, adipocytes and immune cell function toward a protumoral phenotype. TAM: tumor-associated macrophages; T_reg: Regulatory T cells.