Abstract
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.
Highlights
Received: 5 January 2021Glutamine is the most abundant amino acid in the human body, constituting 20%of the total free amino acids in blood [1]
These findings show that cancer-associated fibroblasts (CAFs) increases glutamine synthesis through dysregulated metabolism compared to normal ovarian fibroblasts (NOFs)
The conversion of glutamine to glutamate via glutaminolysis catalyzed by GLS, supports cancer cell proliferation by generating anti-oxidants and macromolecule biosynthesis
Summary
Of the total free amino acids in blood [1]. Cells acquire glutamine from circulation or de novo synthesis by glutamine synthetase (GS). Cancer cells rewire metabolism to facilitate rapid proliferation and maintain survival under harsh conditions, such as nutrient-deprived and poorly vascularized environments (Figure 1) [6,7]. PC: pyruvate PC: carboxylase, glutaminase, GS: glutamine synthetase, methionine thediverse synthesis of diverse macromolecules. Dysregulation of Glutamine Synthetase is in aTumor glutaminase (GLS), and this process is essential for generating energy in various cancer. Cancerand cellsfunctions rely on glutaminolysis andeach cannot survive glutamine-deprived cuses on specific cancer types in which. CB-839, a selective GLS1 inhibitor, Glioma activity in various cancer types, and the clinical trial is ongoing in several has antitumor. Investigated glutamine metabolism in a human orthotopic is disparate depending on cancer subtypes. Cancer cells expressing high GS are self-sufficient for glutamine and can survive in glutamine-deprived conditions. We discuss the GS inhibitors and suggest future directions of GS investigations in cancer
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