The Warburg effect indicates that cancer cells survive through glycolysis under aerobic conditions; as such, the topic of cancer metabolism has aroused interest. It is requisite to further explore cancer metabolism, as it helps to simultaneously explain the process of carcinogenesis and guide therapy. The flexible metabolism of cancer cells, which is the result of metabolic reprogramming, can meet the basic needs of cells, even in a nutrition-deficient environment. Glutamine is the most abundant non-essential amino acid in the circulation, and along with glucose, comprise the two basic nutrients of cancer cell metabolism. Glutamine is crucial in non-small cell lung cancer (NSCLC) cells and serves an important role in supporting cell growth, activating signal transduction and maintaining redox homeostasis. In this perspective, the present review aims to provide a new therapeutic strategy of NSCLC through inhibiting the metabolism of glutamine. This review not only summarizes the significance of glutamine metabolism in NSCLC cells, but also enumerates traditional glutamine inhibitors along with new targets. It also puts forward the concept of combination therapy and patient stratification with the aim of comprehensively showing the effect and prospect of targeted glutamine metabolism in NSCLC therapy. This review was completed by searching for keywords including ‘glutamine’, ‘NSCLC’ and ‘therapy’ on PubMed, and screening out articles.
Lung cancer is the second most common cancer in the world and remains the leading cause of cancer death proven by a high global diagnosis rate (11.4%) and mortality rate (18%). In 2020, there were 19.3 million new cases of cancer and 10 million cancer-associated deaths worldwide, and it was estimated that ~1.8 million of these individuals died of lung cancer (
It has been nearly a century since the first study on tumor metabolism, the Warburg effect, was published in 1924 (
A previous study indicated that NSCLC cells may use glutamine as a substrate through metabolic reprogramming to induce glutamine addiction, which is a promising therapeutic target (
It is widely accepted that metabolic programming is one of the hallmarks of cancer (
The Warburg effect demonstrated that cancer cells use glycolysis in an aerobic environment for rapid proliferation (
Glucose and glutamine are the two basic nutrients used by cancer cells (
Glutamine metabolism has strong heterogeneity, reflected in its close relationship with the origin of the tumor tissue, oncogenes, and the tumor microenvironment (TME) (
The main purpose of glucose metabolism is to generate lactate, which can store a vast amount of carbon, resulting in a reduction of carbon sources entering the TCA cycle and a continuous flow of intermediate TCA cycle products into the cytoplasm for the synthesis of biological macromolecules, such as lipids, nucleotides and proteins; as such, glucose metabolism leads to TCA cycle cataplerosis (
Cell proliferation requires the synthesis of a large amount of proteins, nucleic acids and lipids (
The mTOR signaling pathway promotes the anabolism of biological macromolecules, such as lipids, proteins and nucleotides, by integrating intracellular and extracellular signals, and inhibits autophagy to sustain cell survival (
Glutamine metabolism in NSCLC involves related enzymes and transporters. One of the hallmarks of cancer is the reprogramming of energy metabolism for the regulation of metabolism-related enzymes and transporters at transcriptional or post-transcriptional level (
In BRAFV600E-driven lung adenocarcinoma, autophagy sustains mitochondrial glutamine metabolism, consistent with some ‘autophagy-addicted’ NSCLC cells (
Glutamate is converted into α-KG in two different pathways catalyzed by either transaminase accompanied by the production of other non-essential amino acids, or by GDH1 accompanied by generation of the reducing substance NADPH (
Although the Warburg effect describes the basic pattern of glucose metabolism in tumor cells, tumor heterogeneity indicates that metabolism is not a specific metabolic map (
Glutamine metabolism in NSCLC is heterogeneous; there is higher glutamine consumption and metabolism in AC compared to SCC (
In addition to the classical metabolic substrate, glucose, glutamine is another important nutrient, making cancer cells glutamine-dependent by synthesizing biological macromolecules, supplementing TCA cycle substrates and maintaining redox balance. Simultaneously, it is also one of the hallmarks of NSCLC. Therefore, targeting the transport and metabolism of glutamine will become a promising therapeutic strategy for the treatment of NSCLC (
The first step of glutamine influx or efflux is through the various glutamine transporters (
Key enzymes of the glutamine metabolism process are promising therapeutic targets that have been widely studied, and some mature drugs have been used in clinical treatment (
Surgery, chemotherapy, and radiotherapy are still the first-line treatment approaches for NSCLC; emerging immunotherapy and molecular-targeted therapy approaches also have hopeful prospects (
It is well known that ATP production depends on cytosol NADP; NSCLC cells obtain ATP from cytosol NADH through the malate-aspartate shuttle system using glutamate, which is the catalysate of GLS1. GLS1 inhibitors, such as BPTES, reduce ATP production through glutamate deficiency, and finally inhibit cancer cell growth (
In addition to targeting intracellular metabolic processes, the metabolism of cells in the TME has attracted the interest of researchers because the relationship between cell metabolism and TME is regarded as one of the emerging hallmarks of cancer (
Apart from the traditional targeted drugs that aim at inhibiting glutamine transporters and GLS, an increasing number of promising targets directly or indirectly involved in glutamine metabolic pathway have been studied, with the aims of achieving an antitumor effect by blocking the glutamine-dependent metabolism in tumor cells (
Glutamine-dependency in tumor cells is partly determined by the process of TCA cycle anaplerosis. In MYC-transformed cells, the carbon provided by glutamine enters the TCA cycle mainly through transamination, which exposes the vulnerable points during metabolism and provides an opportunity for targeting the inhibition of transaminase (
Tumor metabolism is not a specific metabolic map, which means that targeted metabolic therapy is not fixed (
Among the Asian population, the proportion of EGFR mutations in lung AC ranges between 45 and 75% (
KRAS-driven cancer accounts for ~35% of lung AC cases (
As the most abundant non-essential amino acid in the circulation, glutamine serves an indispensable role in the metabolism of some tumors. It has an important role in supporting cell growth and proliferation, activating signal transduction pathways, and maintaining redox balance. Since the publication of the Warburg effect, which proposed concept of aerobic glycolysis and glutamine addiction, there has been an increase in the number of studies on tumor metabolism. NSCLC cells are dependent on glutamine through the metabolic reprogramming caused by the mutation of oncogenes or tumor suppressor genes, which makes them unable to grow normally under glutamine deprivation. The metabolic reprogramming of tumor cells can promote cell growth and proliferation, as well as lead to the malignant progress of tumor and the emergence of drug resistance. Recently, targeting the key enzymes and transporters of glutamine metabolism with specific inhibitors showed pharmacological progress and has led to clinical trials, which revealed surprising results regarding treatment (summarized in
This review described the identification of glutamine as a promising target for treatment by emphasizing its role in NSCLC cell metabolism. In addition to the traditional drugs targeting glutamine metabolic enzymes and transporters, new sweet spots, along with the concept of combination and individualized therapy, are also described. Inhibition of glutamine as a targeted therapy for NSCLC is promising, but still faces new challenges. Cancer and normal cells share many pathways, making selective inhibition particularly important. Future studies should not only consider glutamine metabolism in normal cells, but also target glutamine addiction in NSCLC cells, which will maximize the therapeutic effect and reduce side effects. Moreover, the heterogeneity of NSCLC metabolism and the difference in individual gene expression lead to the absence of a metabolic map suitable for everyone. 18F-flurodeoxyglucose provides useful information by tracking glucose metabolism
Although the heterogeneity of cancer metabolism limits the application of metabolism-targeted drugs to some extent, glutamine-targeted therapy still has potential. Glutamine supplement treatment may be beneficial to prevent mucositis in patients receiving radiotherapy and chemotherapy. For example, glutamine can be used to prevent chemotherapeutic or radioactive esophagitis in patients with esophageal cancer (
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LZ, QZha and QZhu wrote the manuscript; YZ and YL revised the manuscript and XH revised and confirmed the final version of the manuscript. All authors read and approved the final version of the manuscript. Data authentication is not applicable.
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The authors declare that they have no competing interests.
Schematic diagram of glutamine metabolism. Glutamine is transported into the cell by SLC1A5 or SLC7A5 and turns into glutamate catalyzed by transaminases or GLS. Glutamate will be catalyzed by GDH to generate α-KG. α-KG can enter into the TCA cycle to complete the process of anaplerosis or be catalyzed by IDH to produce citrate, which leaves mitochondria for the biomass synthesis of fatty acids and amino acids. Glutamine and cystine will synthesize glutathione through a series of catalytic processes to keep redox homeostasis. GLS, glutaminase; GPT, glutamic pyruvic transaminase; GDH, glutamate dehydrogenase; IDH, isocitrate dehydrogenase; FAS, fatty acid synthase; GSH, glutathione (reduced); GSSH, glutathione (oxidized); α-KG, α-ketoglutaric acid; TCA cycle, tricarboxylic acid cycle.
Summary of preclinical tools and clinical therapeutic drugs targeting different process of glutamine metabolism.
First author/s, year | Class | Drug | Mechanism | Stage | Target | (Refs.) |
---|---|---|---|---|---|---|
Magill |
Glutamine analogue | DON | Widely inhibit the glutamine metabolic enzyme | Limited due to toxicity | Enzyme used by glutamine | ( |
Leone |
JHU083 | Pro-drug of DON | Preclinical compound tool | ( |
||
Robinson |
GLS inhibitors | BPTES | Inhibition of GLS | Preclinical tool | GLS | ( |
Gross |
CB-839 | Phase I and II | ( |
|||
Caiola |
Transaminase inhibitors | L-cycloserine | Inhibition of TCA cycle | Preclinical tool | GPT2 | ( |
Moreadith and Lehninger, 1984 | AOA | anaplerosis | Preclinical tool | Aminobutyrate aminotransferase | ( |
|
Hassanein |
Glutamine transporters inhibitors | GPNA | Inhibition of glutamine transport | Preclinical tool | SLC1A5 (also known as ASCT2) | ( |
Wise and Thompson, 2010 | BCH | Inhibition of essential amino acids | Preclinical tool | SLC7A5 (also known as LAT1) | ( |
|
Hu |
Sulfasalazine | Inhibition of cysteine-glutamine transport | Phase II for breast cancer | SLC7A11 (also known as xCT) | ( |
AOA, aminooxyacetate; ASCT2, amino acid transporter 2; BCH, 2-aminobicyclo-(