Glutamine Synthetase as a Therapeutic Target for Cancer Treatment

The significance of glutamine in cancer metabolism has been extensively studied. Cancer cells consume an excessive amount of glutamine to facilitate rapid proliferation. Thus, glutamine depletion occurs in various cancer types, especially in poorly vascularized cancers. This makes glutamine synthetase (GS), the only enzyme responsible for de novo synthesizing glutamine, essential in cancer metabolism. In cancer, GS exhibits pro-tumoral features by synthesizing glutamine, supporting nucleotide synthesis. Furthermore, GS is highly expressed in the tumor microenvironment (TME) and provides glutamine to cancer cells, allowing cancer cells to maintain sufficient glutamine level for glutamine catabolism. Glutamine catabolism, the opposite reaction of glutamine synthesis by GS, is well known for supporting cancer cell proliferation via contributing biosynthesis of various essential molecules and energy production. Either glutamine anabolism or catabolism has a critical function in cancer metabolism depending on the complex nature and microenvironment of cancers. In this review, we focus on the role of GS in a variety of cancer types and microenvironments and highlight the mechanism of GS at the transcriptional and post-translational levels. Lastly, we discuss the therapeutic implications of targeting GS in cancer.

Automated summary

Glutamine plays a crucial role in cancer metabolism, with cancer cells consuming excessive amounts for rapid proliferation, especially in poorly vascularized cancers. Glutamine synthetase (GS) is essential in cancer metabolism as the sole enzyme responsible for synthesizing glutamine, which supports nucleotide synthesis. GS exhibits pro-tumoral features by providing glutamine to cancer cells in the tumor microenvironment, enabling cancer cells to maintain sufficient glutamine levels for catabolism, ultimately supporting cancer cell proliferation.