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Sharma, N. Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. Download references. This work was supported by National Research Foundation of Korea NRF grants NRFR1A2C, R1A5A, NRFR1A2C, and NRFR1C1C funded by the Ministry of Science and ICT.
Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, , South Korea. BK21 FOUR Community-based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, , Korea.
Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, , Korea.
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Download PDF. Subjects Cancer metabolism. Abstract Proliferating cancer cells rely largely on glutamine for survival and proliferation. Introduction Metabolic reprogramming, a hallmark of cancer cells, is a process by which cancer cells ensure a sufficient supply of proteins, nucleotides, and lipids to support rapid growth and proliferation 1.
The role of glutamine in cancer cell growth Rapidly proliferating cancer cells take up glutamine from plasma via various amino acid transporters, and then it is converted to glutamate in the mitochondria by the two forms of glutaminase: kidney-type glutaminase GLS 1 and liver-type GLS2 8.
Full size image. Targeting glutaminase and transaminase as a treatment for cancer GLS, which is highly expressed in cancer cells and plays a role in cancer progression, has been investigated extensively as a druggable target Role of glutamine metabolism in redox homeostasis ROS levels are elevated persistently in proliferating cancer cells, and ROS damage DNA and cellular components; therefore, redox homeostasis plays a pivotal role in protecting cancer cells against them.
Targeting redox homeostasis for cancer treatment Approximately one-third of glutamine taken up by human fibroblast cells is exchanged for cysteine by SLC7A11 59 , Targeting glutamine transporters as a treatment for cancer Cancer cells require an abundant supply of glutamine from the extracellular milieu; therefore, upregulation of glutamine transporters SLC1A5, SLC38A1, SLC38A2, and SLC6A14 at the cell membrane is required Fig.
SLC1A5 SLC1A5 ASCT2 is an obligatory sodium-dependent transporter of neutral amino acids, which are exchanged for asparagine, threonine, or serine SLC38A1 and SLC38A2 SLC38A1 SNAT1 and SLC38A2 SNAT2 are sodium-dependent neutral amino acid transporters that drive glutamine influx into cells Mechanisms that induce resistance to glutamine-targeting therapies Although targeting glutamine metabolism is a promising therapeutic approach, few drugs have been developed.
Effects of targeting glutamine metabolism in the TME The TME is a complex milieu that surrounds tumor cells, often providing immunosuppressive cover that facilitates immune invasion. Glutamine metabolism in immune cells Accumulating evidence shows that glutamine is an immunomodulatory nutrient in immune cells.
Glutamine blockade in the TME The metabolism of cancer cells and immune cells in the TME is regulated by cell-intrinsic programs through mTORC1 signaling Conclusion Glutamine metabolism plays a central role in regulating uncontrolled tumor growth by modulating bioenergetic and redox homeostasis and by serving as a precursor for the synthesis of biomass.
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Article PubMed Google Scholar Vanhove, K. Article PubMed PubMed Central Google Scholar Yang, M. A similar study has shown that the high expression of GLS1 in HCC had a markedly shorter overall survival time than its low expression Prostate cancer Pca treatments, such as radiation, chemotherapy, and hormone therapy, can induce autophagy that improves therapeutic resistance 70 — Existing evidence has linked the Gln metabolism to autophagy through oxidative homeostasis in Pca.
For instance, a recently published article showed that the radio-resistant Pca cells strongly rely on Gln metabolism to maintain oxidative homeostasis.
However, Pca cells could trigger autophagy upon Gln withdrawal and do not exhibit significant radio-sensitization Upon further investigations, the researchers found that the ionizing radiation-derived ROS can induce autophagy as a stress response of Pca cells, but it is neutralized by GSH and NADPH produced by Gln metabolism.
When blocking Gln metabolism, Pca cells could activate the ATG -mediated autophagy as a survival strategy to withstand radiation-induced damage due to GSH depletion and ROS accumulation 73 , Consistently, other studies also confirmed that autophagy inhibition increases ROS production in Pca cells 75 — Overall, Gln metabolism affects the autophagy of Pca cells by affecting the level of ROS.
There is growing evidence that clear cell renal cell carcinoma cells ccRCCs are Gln-addicted that is reprogrammed to feed an intrinsic antioxidant system 82 — To further confirm the role of Gln as a source for the GSH pathway, absolute quantitative GSH and GSSG levels in cells grown with and without Gln were compared.
The result showed that GSH and GSSG levels were markedly reduced in the Gln-depleted group, which confirms the necessity of Gln for maintaining oxidative homeostasis of ccRCCs In addition, an interesting study shows that the suppression of fatty acid metabolism by inhibition of β-oxidation lead to the RCC cells dependent on the Gln-GSH pathway to prevent lipid peroxidation and ferroptosis Notably, high GSH levels have proven to be a key feature of high-grade, high-stage and metastatic ccRCCs 81 , All in all, these data suggest that Gln-dependent antioxidant effects may provide ccRCCs with a critical mechanism for their survival.
In general, Gln is an antioxidant defense only in Gln addicted cancers, but not in all cases. Oligodendroglioma cells lack Gln synthetase a marker of Gln-addicted cancers , but are independent of extracellular Gln thus are not Gln addicted 89 , However, a previous study showed that small amounts of extracellular Gln are sufficient for oligodendroglioma cells growth.
Gln starvation does not significantly affect the cell content of anaplerotic substrates, but causes a significant decrease in the intracellular content of GSH in oligodendroglioma cells This result means that Gln addiction and Gln roles as antioxidants are not correlated.
In light of the findings mentioned above, it would seem reasonable to expect that Gln metabolism plays an important role in maintaining ROS levels in cancer cells.
However, we noted that most of the above-mentioned studies have mainly focused on the effects of Gln metabolism on maintaining oxidative homeostasis of cancer cells, whereas these effects were not suitable for every situation.
Some studies have shown that the anaplerotic role of Gln metabolism in replenishing the TCA cycle intermediates could enhance ROS production under the blocking of GSH synthesis 92 — For instance, a recently published article showed that Gln metabolism was crucial to maintaining cystine starvation-induced mitochondrial membrane potential MMP hyperpolarization, accompanied by an increase in electron transfer chain ETC activity and lipid ROS generation to promote ferroptosis In support of this notion, data from various studies showed that inhibiting the glutaminolysis can suppress TCA cycle and MMP hyperpolarization, and reduce lipid ROS production, thus enhancing ferroptosis resistance 95 — Similarly, various studies showed that inhibiting xCT activities could suppress Gln-derived Glu export and enhance Glu to replenish the TCA cycle intermediates 99 — Therefore, it has been theorized that inhibition of xCT activities could promote Glu to replenish the TCA cycle intermediates, which could promote ROS production Figure 4.
All in all, increasing ROS levels by Gln metabolism under blocking of GSH synthesis promoted ferroptosis, which may provide a novel treatment guideline for ferroptosis-based tumor therapy.
Figure 4 Gln metabolism promotes ROS production through the TCA cycle. PUFA-PLs, Polyunsaturated fatty acid chain s. The demonstration of the link between Gln metabolism and oxidative homeostasis of cancer has prompted research into strategies to target Gln metabolism to damage oxidative homeostasis of cancer.
In this regard, GLS inhibitors aimed at decreasing Gln metabolism and impairing oxidative homeostasis are attracting increasing clinical interest. Many small molecules have been assayed to block GLS isoenzymes after the first attempt and failure to use 6-diazooxo-L-norleucine DON as an anti-cancer drug , The bis 5-phenylacetamido-1,2,4-thiadiazolyl ethyl sulfide BPTES and CB are the specific inhibitors most frequently Notably, CB is currently being administered to humans in phase 1 clinical trials for some types of cancers 49 , — However, because of the plasticity of adaptive metabolic reprogramming in cancer cells, successful single treatments against cancers are scarce 4 , — Therefore, some specific inhibitor of Gln metabolism has reached better results in sensitizing cancer cells to other treatments Targeting Gln metabolism combined with drugs that are strong inducers of mitochondrial ROS, is widely used for treating multiple cancers Table 1.
For instance, dihydroartemisinin cooperatively induces excessive intracellular ROS resulting in profound apoptosis when combined with CB in HCC In a similar study, Gregory et al. demonstrated that a combination of GLS inhibition with ATO or HHT showed great activity against AML Preclinical studies have also reported a benefit when combined with Gln metabolism inhibitors and radiotherapy.
For example, the inhibitor CB increased GSH depletion, and enhanced the radiation sensitivity of lung tumor cells xenografts in mice Interestingly, one recent study showed that the combination of Gln metabolism inhibitors with radiotherapy could activate the ATG5-mediated autophagy of Prostate cancer, and proposes a strategy that a combination with autophagy inhibition and the blockade of Gln metabolism makes Pca radio-sensitization 73 , 74 , However, it remains controversial whether antioxidants affect treatment outcomes or whether antioxidants ameliorate adverse effects induced by chemotherapy and radiotherapy, which needs further investigations in the future In conclusion, combination therapy, including inhibitors of Gln metabolism, may be a promising strategy for cancer cells.
Table 1 Combined treatments: targeting glutaminolysis in combination with drugs that unbalance mitochondrial redox state. The antioxidant capacity of tumor cells is required for rapidly proliferating and aggressive cancer cells to adapt to hypoxia and excessive ROS levels.
The literature reviewed here suggests that Gln has been established as an important factor in maintaining the oxidative homeostasis of cancer cells. Targeting Gln metabolism impaired oxidative homeostasis of cancer cells and may provide effective approaches for therapies against cancer.
Future studies on Gln metabolism in maintaining oxidative homeostasis may provide novel and effective therapeutic strategies to treat a subset of cancer patients. Conceptualization, YD, WL, and TG; writing—original draft preparation, TG, CZ, XO, JZ, JY, and SC; writing—review and editing, YD and WL; visualization, YD.
All authors have read and agreed to the published version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Journal Article. Glutamine Metabolism, Sensing and Signaling in Plants Get access. Kim-Teng Lee , Kim-Teng Lee.
Institute of Plant and Microbial Biology, Academia Sinica. Molecular and Biological Agricultural Sciences, The Taiwan International Graduate Program, Academia Sinica. Oxford Academic. Google Scholar. Hong-Sheng Liao. Ming-Hsiun Hsieh. Revision received:. Editorial decision:.
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Abstract Glutamine Gln is the first amino acid synthesized in nitrogen N assimilation in plants. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved.
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Qnd Gln is the Heart health support services amino acid synthesized in ane N assimilation Refuel and recharge plants. Plants have multiple GS isoenzymes that work Glutaminf or cooperatively to ensure adn the Gln supply Glutamine and metabolism sufficient for plant growth metabolsm development under Glutamine and metabolism Gutamine. Gln Glutqmine a Glutamine and metabolism block for protein synthesis and an N-donor for the biosynthesis of amino acids, nucleic acids, amino sugars and vitamin B coenzymes. Most reactions using Gln as an N-donor are catalyzed by Gln amidotransferase GAT that hydrolyzes Gln to Glu and transfers the amido group of Gln to an acceptor substrate. Several GAT domain—containing proteins of unknown function in the reference plant Arabidopsis thaliana suggest that some metabolic fates of Gln have yet to be identified in plants. In addition to metabolism, Gln signaling has emerged in recent years.
Glutamine and metabolism -
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This study was financially supported by the National Natural Science Foundation of China , , Taishan Scholar Program of Shandong Province tsqn , Shinan District Science and Technology Program of Qingdao YY.
Department of Urology, The Affiliated Hospital of Qingdao University, No. Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, , China. Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, , China.
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Reprints and permissions. Ma, G. et al. Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment. Cell Commun Signal 20 , Download citation. Received : 06 April Accepted : 31 May Published : 27 July Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Abstract Metabolic reprogramming and immune escape play a major role in tumorigenesis.
Video abstract. Overview of glutamine metabolism in tumor and immune cells Glutamine metabolism in tumor cells Glutamine is the most abundant and widely used amino acid in the human body, which is an important source of nitrogen, and the respiratory fuel for tumor cells. Glutamine metabolism in immune cells Metabolic reprogramming plays a major role in: a the activation of immune cells; b the regulation of immune cell phenotype and function; c mounting a robust anti-tumor immune response [ 43 , 44 , 45 ].
Glutamine metabolic association between tumor cells and immune cells Glutamine competition Like cancer cells, immune cells in the TME also undergo metabolic reprogramming [ 44 ]. Full size image. Effects of glutamine metabolism on immune response Metabolic reprogramming of glutamine metabolism in tumor cells and its impact on immune response Glutamine metabolism maintains tumor survival and progression, and is very important for multiple biological processes such as nucleotide synthesis, amino acid production, protein glycosylation modification, extracellular matrix production, epigenetic modifications, maintenance of cellular redox balance, and autophagy [ 68 ].
Conclusions The critical role of glutamine in energy generation and macromolecule synthesis underlies its importance in tumor progression and immune response.
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Glutamine is the most abundant amino acid in blood andd tissues, and Fat metabolism foods most important nutrient except Glutamine and metabolism glucose Gluttamine cancer cells. Over Fat metabolism foods Anti-aging nutrition years, most Glutaminf have focused on the role of Gln metabolism in jetabolism energy metabolism rather than maintaining oxidative Glutamije. Here, Fat metabolism foods mftabolism will review the recent scientific literature about the link between Gln metabolism and oxidative homeostasis, with an emphasis on the potential role of Gln metabolism in different cancers. Given that oxidative homeostasis is of critical importance in cancer, understanding the impacts of a Gln metabolism on oxidative homeostasis, gaining great insights into underlying molecular mechanisms, and developing effective therapeutic strategies are of great importance. The reactive oxygen species ROSwhich mainly comes from the mitochondrial membrane as a byproduct of OXPHOS and nicotinamide adenine dinucleotide oxidases NOXscannot avoid being produced in cellular metabolism 1 — 4.
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