The consumption of the amino acid glutamine in cancer is somewhat of a conundrum. We know adequate glutamine levels are needed for ensuring nitrogen balance, maintaining gut integrity, and beneficially influencing our immune system. All positive things for promoting health and wellbeing.
On the other hand, cancer cells are avid consumers of glutamine with the amino acid being a pivotal driver in tumor progression. Glutamine contributes to essentially every core metabolic task of developing cancer cells; being metabolised for fuel, providing nitrogen for protein and nucleotide synthesis, and having specific cancer promoting functions. In fact, as we are about to see, glutamine is a critical player in thwarting the efforts of our innate defensive systems to destroy cancer cells.
1) Glutamine Blocks Oxidative Stress
We've all been fed the dietary anti-oxidant yarn; how free radicals are bad for us causing deleterious effects and damaging cells, and we should do all we can to block them. And, glutamine is both a precursor and a regenerating source of the major intracellular antioxidant glutathione. But, free radicals have a pivotal role in cell regulation, one of these being what is known as "oncogenic stress" - a failsafe in cell mutation - in which an increased amount of intracellular free radicals in cancer cells instigates a DNA damage response causing cell death. However, with a plentiful intracellular glutamine supply to produce glutathione, cancer cells are able to resist this increase in oxidative stress.
2) Glutamine Stops Cell Repair
Macroautophagy is the degradation/recycling of unnecessary and dysfunctional cellular components; in essence a vital repair mechanism for responding to cell damage. Autophagy is a catabolic process, its initiation activated by metabolic stress such as a low fuel availability (this is one of the key mechanisms through which the benefits of intermittent fasting are believed to be conferred). A key regulator of autophagy is a signalling protein, called mTORC1, which when activated (in the presence of essential amino acids) initiates protein synthesis and suppresses autophagy. With cancer cells modified to uptake glutamine amounts in excess of their metabolic need, some of this excess is shuttled back out of the cell in exchange for essential amino acids, activating mTORC1 and turning off cell autophagy.
3. Glutamine Buffers the Cell
A hallmark of the rapid proliferation of cancer cells is the metabolism of glucose and glutamine to lactate for fuel. Cells need to be kept at a minimum pH for survival, but with cancel cells dependent on the production of the acidic lactate, the intracellular pH will be lowered to a detrimental level, unless a substrate is available to effectively neutralise this excess acid production. In the metabolism of glutamine ammonia is produced, and it has now being hypothesised that this ammonia production is key in the cancer cell's acid resistance and for ensuring its survival. Ammonia is also believed to increase the stress resistance of the cancer cell.
Glutamine is the ambrosia for cancer cells; being more than "just" fuel for the cell growth engine, but also a multi-functional regulator of cellular activities, essential for adaptation, survival and progression. Such is the demand by certain cancer cells that they cannot survive without a continuous supply of glutamine - known as "glutamine addiction"- and glutamine blockers have become a promising target for the future of cancer treatment.
Thus, it may come as no surprise that many recommendations exist for cancer patients to steer clear of glutamine. But here's the thing, such is the efficiency of the glutamine sourcing machinery of the cancer cells, that they will always have enough from the glutamine that is produced in the body. It is our healthy cells which become depleted and lose out. For example, with low glutamine comes low glutathione in our natural killer cells impeding their ability to defend our healthy cells and promote immune function which may be necessary in the cancer battle. With more than 90% of the body's glutamine supply in muscle, this will become heavily depleted creating a serious negative nitrogen balance. It seems likely that this depletion is tied to the common occurrence of cachexia and that supplementation of glutamine could confer great benefit. The clinical importance of cachexia is emphasised by the fact that it is the principal cause of death in about one third of cancer patients. While academic consensus still does not exist, a large body of evidence is now available to support glutamine supplementation in cancer patients; improving clinical outcome and quality of life, as well as reducing the risks of high dose chemotherapy and radiation.
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