Author:Si tie
Since the publication of Otto Warburg's groundbreaking research - the aerobic glycolysis theory, glucose metabolism has been a top priority in cancer metabolism research. Studies of other metabolites, such as glutamine, have been shelved until recently in recent decades.
In 1935, Hans Krebs proposed the famous tricarboxylic acid cycle (TCA), pointing out the importance of glutamine metabolism in animals. Subsequent studies have shown that glutamine plays an important role in the growth of normal cells and cancer cells.
In view of the key role played by glutamine in energy production and macromolecular synthesis, related drugs developed for glutamine have great potential for inhibiting tumors. Below we will introduce the physiological effects of glutamine and the clinical progress of inhibitors.
Glutamine metabolism
The high level of glutamine in the blood provides a ready-made carbon and nitrogen source to support the biosynthesis, energy metabolism and homeostasis of cancer cells and promote tumor growth.
Glutamine is transported into cells by the transporter SLC1A5 (solute carrier family 1 neutral amino acid transporter member 5) in the cell.
Under conditions of nutrient deficiency, cancer cells can obtain glutamine by breaking down macromolecules. Over-activation of the oncogene RAS can promote pinocytosis, cancer cells scavenge extracellular proteins, degrade into amino acids including glutamine, and provide nutrients for cancer cells.
Cancer cells absorb large amounts of glucose, but most carbon sources produce lactic acid through aerobic glycolysis rather than in the TCA cycle.
Tumor cells that overactivate the PI3K, Akt, mTOR, KRAS gene or MYC pathway stimulate glutamate metabolism to produce alpha-ketoglutarate by glutamate (GLUD) or transaminase catalysis. Alpha-ketoglutarate enters the tricarboxylic acid (TCA) cycle and provides energy to the cells.
Synthesis of glutamine in nucleic acids, lipids and proteins
Glutamine can be used as a raw material for biosynthesis during cell growth and division. Carbon from glutamine can be used for the synthesis of amino acids and fatty acids, and nitrogen from glutamine acts directly on the biosynthesis of purines and pyrimidines.
Nucleic acid synthesis
Aspartic acid produced by TCA cycle and transamination acts as a key carbon source for the synthesis of purines and pyrimidines. Glutamine-deficient cancer cells are arrested in the cell cycle and cannot be used for nucleic acid synthesis by TCA circulating intermediates such as oxaloacetate. However, supplemental exogenous nucleotides or aspartic acid can alleviate cell cycle arrest caused by glutamine deficiency.
In addition, the glutamine-dependent mTOR signal activates the enzyme carbamyl phosphate synthetase 2, aspartate transferase, and carbamoyl aspartate dehydratase (CAD), which catalyzes the conversion of glutamine-derived nitrogen into pyrimidine. Synthesis of
precursors.
Lipid synthesis
Glutamine is catalyzed by glutaminase (GLS or GLS2) to produce glutamate, which is then catalyzed by glutamate (GLUD) or a transaminase to produce alpha-ketoglutaric acid. Alpha-ketoglutarate produces acetyl-CoA by catalytic reverse, which can be used for direct synthesis of lipids.
Protein synthesis
In addition to the carbon in glutamine for amino acid synthesis, glutamine plays a key role in protein synthesis. Lack of glutamine leads to incorrect protein folding and endoplasmic reticulum stress response.
Glutamine can be synthesized by uridine diphosphate acetylglucosamine (UDP-GlcNAc), a substrate for β-O-acetyltransferase (OGT), which plays an important role in protein folding in the endoplasmic reticulum. The role.
GCN2, a serine threonine kinase, a regulatory domain fragment, is similar to histidine-tRNA synthetase. The combination of glutamine and histidine-tRNA synthetase inhibits the activity of the GCN2 enzyme. The latter played an important role in the overall stress response.
Glutamine and autophagy
The relationship between autophagy and glutamine is complex, which is also reflected in the role of autophagy in tumor development.
The role of autophagy in tumors is contradictory: in some cases, it inhibits oxidative stress, leads to chromosomal instability, and inhibits tumor development. Autophagy can also support the survival of cancer cells by promoting pinocytosis and inhibiting stress pathways such as p53.
Glutamine inhibits the activation of GCN2 and comprehensive stress, and ammonia produced from glutamine promotes the development of autophagy in both autocrine and paracrine modes.
ROS can induce autophagy as a stress response, but is neutralized by glutathione and NADPH produced by glutamine metabolism. Glutamine can also indirectly stimulate mTOR, which in turn inhibits autophagy through complex mechanisms.
Glutamine and ROS
Reactive oxygen species (ROS)-mediated cell signaling can promote tumor development at a certain physiological level, but when the level is too high, reactive oxygen species can cause great damage to macromolecules in cells. ROS are produced in several ways, in which the mitochondrial electron transport chain produces superoxide (O2−) anions.
However, tumors can control ROS levels through products produced by the glutamine metabolic pathway, preventing high levels of ROS from causing chromosomal instability. The most important way for glutamine to control reactive oxygen species is to synthesize glutathione. Glutathione is a tripeptide that can be used to neutralize peroxyl radicals.
Glutamine can also affect the balance of reactive oxygen species through NADPH. Glutamate produces a series of reactions of malic acid, which is catalyzed by malic enzyme to produce NADPH, which is used to regulate the balance of ROS.
Clinical application of glutaminase inhibitors
The dependence of tumor cells on glutamine metabolism makes it a potential anticancer target. Many compounds targeting glutamine metabolism have been the focus of research from initial transport to subsequent conversion to alpha-ketoglutarate.
Although most of them are still in the pre-clinical "tool synthesis" phase or are limited by the toxicity of the compounds, glutaminase (GLS) allosteric inhibitors show great potential in preclinical cancer models, a very active compound, CB-839 has entered clinical trials.
There are two main types of glutaminase in the human body: kidney glutaminase (GLS) and liver glutaminase (GLS2).
Tumor cells over-activated renal glutaminase (GLS), which acts primarily on non-cancer cells to catalyze the metabolism of glutamine.
The pleiotropic effects of glutamine in cell function, such as energy synthesis, macromolecular synthesis, mTOR activation, and reactive oxygen species balance, make GLS inhibitors synergistic in combination therapy.
Inhibition of the glutaminase gene prevents the transition of epithelial cells to mesenchymal cells. This step is a key step in tumor cell invasion and eventual metastasis. Therefore, in the combination therapy of glutamine metabolism inhibition, prevention of metastasis may be a GLS inhibitor. Play an important role in the anti-cancer effect.
Tumor immunization has also become the most promising treatment to date, such as by blocking the immunological checkpoint PD-1 mAb or using engineered chimeric antigen receptor (CAR) T cells.
These methods require immune cells to function in the tumor microenvironment, and metabolic inhibitors in vivo may also affect immune function. Recent studies have shown that immune cells compete with cancer cells for glucose, and glutamine may be a similar mechanism.
In fact, glutamine metabolism plays an important role in the activation of T cells and in the regulation of the transformation of CD4+ T cells into inflammatory subtypes.
Glutamine is critical for the activation of cancer-killing T cells. By blocking the glutamine pathway in cancer cells, the amino acid content of the tumor microenvironment is increased, and the killing effect of immune cells is enhanced.
The combination of GLS inhibitor CB-839 and tumor immunity has also entered clinical phase one.
Tumor microenvironment metabolites and tumor immunity have also become the scent of tumor metabolism, and the recent hot IDO inhibitors are among them.
Conclusion
Ninety years ago, Warburg discovered that many animal and human tumors have a very high affinity for glucose, breaking down large amounts of glucose into lactic acid. He also pointed out that cancer is caused by metabolic changes and loss of mitochondrial function.
In addition to the critical role of glucose in the physiological mitochondrial oxidative function of cancer, glutamine plays an important role in tumor cell growth. These arbitrary views have been replaced and improved in the past few decades.
Pleiotropic effects of glutamine in cell function, such as energy synthesis, macromolecular synthesis, mTOR activation, and reactive oxygen species balance.
Tumor cells over-activated renal glutaminase (GLS), whereas normal cells catalyze the metabolism of glutamine as hepatic glutaminase (GLS2). It is possible to selectively develop GLS inhibitors clinically.
Targeting inhibition of some oncogenes makes tumor cells dependent on glutamine, so the combination of targeted inhibitors and glutamine metabolism plays a synthetic lethal effect.
Due to the complexity of the pathogenesis of tumors and the uncertainties of glutamine in human physiological mechanisms, such as 13 years, Professor Shi Yigong of Tsinghua University pointed out that the main role of glutamine metabolism is to produce amines to fight the acidic environment of tumors. Therefore, the combination of GLS inhibitors and other targets has become a trend of development.
References:
[1] Altman B J, Stine Z E, Dang C V. From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy [J]. Nature Reviews Cancer, 2016, 16(10): 619.
[2] Mullard A. Cancer metabolism pipelinebreaks new ground[J]. Nature Reviews Drug Discovery, 2016, 15 (11):735.
[3] Huang W, Choi W, Chen Y, et al. A proposedrole for glutamine in cancer cell growth through acid resistance [J]. CellResearch, 2013, 23 (5): 724.
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