Starve Cancer Cells of Glutamine: Break the Spell or Make a Hungry Monster?

Abstract

Distinct from normal differentiated tissues, cancer cells reprogram nutrient uptake and utilization to accommodate their elevated demands for biosynthesis and energy production. A hallmark of these types of reprogramming is the increased utilization of, and dependency on glutamine, a nonessential amino acid, for cancer cell growth and survival. It is well-accepted that glutamine is a versatile biosynthetic substrate in cancer cells beyond its role as a proteinogenic amino acid. In addition, accumulating evidence suggests that glutamine metabolism is regulated by many factors, including tumor origin, oncogene/tumor suppressor status, epigenetic alternations and tumor microenvironment. However, despite the emerging understanding of why cancer cells depend on glutamine for growth and survival, the contribution of glutamine metabolism to tumor progression under physiological conditions is still under investigation, partially because the level of glutamine in the tumor environment is often found low. Since targeting glutamine acquisition and utilization has been proposed to be a new therapeutic strategy in cancer, it is central to understand how tumor cells respond and adapt to glutamine starvation for optimized therapeutic intervention. In this review, we first summarize the diverse usage of glutamine to support cancer cell growth and survival, and then focus our discussion on the influence of other nutrients on cancer cell adaptation to glutamine starvation as well as its implication in cancer therapy.

Effects of Glucose Deprivation on ATP and Proteoglycan Production of Intervertebral Disc Cells under Hypoxia

“…Another mechanism for cells to resist metabolic stress is to utilize amino acids as an alternative energy source [55][56][57] . For instance, as the most abundant free amino acids circulating in plasma 58 , glutamine is a ready source of carbon and nitrogen to support biosynthesis of nucleotides and amino acids 59,60 . It is well documented that rapidly proliferating cancer cells satisfy their high energy demands by compensating their aerobic glycolysis with glutaminolysis under hypoxia 61,62 .…”

The emerging role of targeting cancer metabolism for cancer therapy

“…93,94 In addition, glutamine is considered as a fuel for TCA cycle via a-ketoglutarate (a-KG) resulting in ATP production. 95 Besides, glutamine reduces oxidative stress by generating NADPH and biosynthesis of glutathione, 96 and it has a key role in cellular antioxidative mechanisms. 97 Glutamine can also regulate energy generation, redox homeostasis, and intracellular signaling.…”

Causes and Consequences of Variable Tumor Cell Metabolism on Heritable Modifications and Tumor Evolution

“…This may pose the opportunity to target glutamine metabolism as a cancer therapeutic, an idea that has drawn enough attention to warrant various reviews on that subject alone (63,64). Although this may seem like a rational therapeutic target, cautionary narratives have been proposed as to the possible outcome of creating a resistant cellular population with a heightened metabolic capacity (65). While glutamine metabolism is non-essential in a normally proliferating cell, under periods of rapid proliferation, like tumor growth, glutaminolysis is an essential process (66).…”