Glutamine Metabolism in Cancer Treatment
Glutamine Metabolism in Cancer Treatment
Glucose and the amino acid glutamine are the two most important nutrients used by cancer cells for their proliferation and growth. While the glycolonic pathway produces ATP and metabolic intermediates, the metabolism of glutamine can provide amino acids, nucleic acids and glutathione necessary for cell proliferation.
Among the various characteristics of cancer, metabolic transformation plays a key role in adapting cancer cells in a changing environment. Cancer cells carry ontigenic mutations, leading to an increase in nutrient uptake and altering their metabolism to support anabolic processes for cell growth and proliferation.
Among the various characteristics of cancer, metabolic transformation plays a key role in adapting cancer cells in a changing environment. Cancer cells carry ontigenic mutations, leading to an increase in nutrient uptake and altering their metabolism to support anabolic processes for cell growth and proliferation.
In order to ensure rapid cell proliferation, cancer cells must first increase nutrient intake from the extracellular environment. Glucose and glutamine are two essential nutrients that absorb cancer cells from the extracellular environment. Cancer cells become easily “addicted” to glucose and glutamine, as their withdrawal can cause cell death. Through the catabolism of glucose and glutamine, the cells produce both carbon intermediates as building blocks for the production of macromolecules and the production of ATP.
The increase in glucose consumption by cancer cells was first described by Warburg who saw that cancer cells consume 10 times more glucose than non-proliferable normal cells and convert glucose into lactate, even in the presence of oxygen and fully functioning mitochondrial respiration. The so-called “Warburg effect” (or aerobic glycolysis) has become a known and common metabolic phenotype that allows tumors to fulfill the energy requirements for cellular growth.
Cancer cells acquire tumor changes to increase glucose uptake and the PI3K/AKT pathway promotes the expression of the GLUT1 glucose transporter. In addition, Akt enhances the potency of the enzymes {hexokinase and Fwsfofroyktokinasi} in order to cause glucose consumption.
Demand for high glutamine was first described in Kall/to cells requiring 10 to 100 times more glutamine than any other amino acid. Glutamine is a source of carbon and nitrogen for de novo biosynthesis of different components containing nitrogen {amino acids} but also participates in the intake of essential amino acids from the extracellular environment. The main regulator of using glutamine is the C-myc transcription factor , which is often adjusted upwards in the proliferator cells[.
Metabolic Intermediates for biosynthesis
Despite the initial idea of Warburg 0that aerobic glycolysis originated as a consequence of mitochondrial dysfunction, subsequent studies have shown that the mitochondria of cancer cells are still functional and capable of conducting oxidative phosphorlation. To adapt to a rapid multiplication, cancer cells need building blocks, intermediate metabolites that only glycolysis can provide by providing glycololytic intermediates such as the PENICILLIN phosphate (PPP) route that often It's hyperexpressed in cancer.
After feeding all the branch pathways, the excess of glycolic flow is converted into lactate to maintain an adequate NAD + reservoir for glycolysis and to avoid inhibition of the tricarboxylic acid cycle (TCA) due to the excess NADH. In addition to glycolic intermediates, the intermediate TCA cycle is also used for accumulation of biosynthetic precursors with the first example the acetyl-COA The production of which is increased BY the enzyme ATP-citrate LYASE (acly) mediated BY PI3K/AKT.
Demand for high glutamine was first described in Kall/to cells requiring 10 to 100 times more glutamine than any other amino acid. Glutamine is a source of carbon and nitrogen for de novo biosynthesis of different components containing nitrogen {amino acids} but also participates in the intake of essential amino acids from the extracellular environment. The main regulator of using glutamine is the C-myc transcription factor , which is often adjusted upwards in the proliferator cells[.
Metabolic Intermediates for biosynthesis
Despite the initial idea of Warburg 0that aerobic glycolysis originated as a consequence of mitochondrial dysfunction, subsequent studies have shown that the mitochondria of cancer cells are still functional and capable of conducting oxidative phosphorlation. To adapt to a rapid multiplication, cancer cells need building blocks, intermediate metabolites that only glycolysis can provide by providing glycololytic intermediates such as the PENICILLIN phosphate (PPP) route that often It's hyperexpressed in cancer.
After feeding all the branch pathways, the excess of glycolic flow is converted into lactate to maintain an adequate NAD + reservoir for glycolysis and to avoid inhibition of the tricarboxylic acid cycle (TCA) due to the excess NADH. In addition to glycolic intermediates, the intermediate TCA cycle is also used for accumulation of biosynthetic precursors with the first example the acetyl-COA The production of which is increased BY the enzyme ATP-citrate LYASE (acly) mediated BY PI3K/AKT.
The TCA cycle also provides metabolic precursors for the synthesis of non-essential amino acids, such as aspartate and Asparaginine from oxaloacetate, or proine and arginine from alpha-ketoglutarate. Then, the aspartate is used for biosynthesis of nucleotide. In fact, the activation of aspartation synthesis is an essential role of oxidative phosphorylosis in cell proliferation[ 30 , 31 ] .
The primary substitute source in the developing cells is glutamine or which is the most abundant free amino acid in the blood and a naturally occurring source of carbon and nitrogen for the proliferation of cancer cells. Glutamine uptake is increased especially in cancer cells that have maladjusted oncogenes and tumour suppressor { C-my} c.
Glutamine is converted to {glutinolysis} in glutamic acid {from GLS} and finally to a-ketoglutarate which enters the TCA cycle to reconstitute the mass of mitochondrial citrate
Glutamine can be synthesized by cells via GLUL/glutamine Synthynine (GS) which catalyzes the condensation reaction between glutamate and ammonia in a way dependent by ATP and produces glutamine. The GS is mainly expressed in the liver, brain and muscles. GS has been found to be an index of hepatococytic carcinoma (HCC) and increased expression is associated with poor survival in glioblastoma.
Carbon
The incorporation of carbon from glutamine into the TCA cycle is essential for the bioenergetic needs and biosynthetic precursors of cells. A-ketoglutarate from glutamine can cause fatty acid synthesis through Isocellular dehydrogenase (IDH). IDH catalyzes the oxidative decarboxylation of isocellular salt for the production of α-ketoglutarate.
Nitrogen donor
Glutamine {has two atoms nitrogen, a and C-nitrogen} acts as a nitrogen donor and is used in the production of Uracil, Thyine, Cysein, adenine and guanine. Interestingly, only the C-nitrogen of glutamine is used for the synthesis of nucleotide.
Glutamine is the source of at least 50% of non-essential amino acids used in the synthesis of proteins from cancer cells. .
During ontogenesis, cancer cells continually face oxidative stress and in order to maintain oxidative homeostasis, cells need to increase their antioxidant ability with the metabolism of glutamine to play an important role in the antioxidant mechanisms. Glutamate derived from glutamine is used in the synthesis of glutathione (glutathione Synthethonis) and glutamine deprivation decreases the glutathione concentration of transformed cells . Glutamine oxidation supports the redox homeostasis WITH NADPH production which is used not only for lipid synthesis, but for the reduction of oxidized glutathione (GSSG), protecting cells from oxidative stress
Chromatin
The metabolism of glutamine not only produces building blocks and energy for cell growth, but it produces substrates for waterfalls that regulate the organization of chromatin. A-ketoglutarate derived from Glutamine is a Co-substrate of dixygenase enzymes to regulate hisone and methylation of DNA. Therefore, the metabolism of glutamine plays a role in gene expression through the contribution of α-ketoglutarate and electrical salt to the modification of the chromatin structure.
Cancer addiction to Glutamine
Due to the high demand for cancer cells for glutamine, the metabolism of glutamine is largely regulated in order to maintain cellular biosynthesis and cellular growth.
The first mechanism to enhance glutamine acquisition is to induce glutamine uptake. Different glutamine carriers contribute to glutamine uptake
And the potency of GLOYTAMINOLYTIKWN enzymes, GLS and GDH, are also regulated strictly.
When the level of extracellular glutamine is limited, some cancerous cell lines are capable of inducing GS expression in order to escape from cell death caused by glutamine deficiency. The GS was found to be hyperexpressed in certain types of cancer, such as breast cancer or glioblastoma, promoting cell proliferation the transcription of GS is activated with different oncology pathways, such as PI3K-PKB-FOXO, C-Myc and Yap1/Hippo[
Glutamine addiction occurs when cancer cells undergo cell death in conditions of glutamine restriction or when the metabolism of glutamine is inhibited. Many tumor cells which rely on glutamine catabolism to build blocks and energy have been reported to be addicted to glutamine. Glutamine-dependent cells are experiencing decreased survival or are still subjected to a deptotic cell death, associated with increased DNA damage, overproduction of ROS or reduced ratio of reduced/oxidized glutathione (GSH/GSSG). In this context, the onparent transcriptional factor C-Myc plays a key role in the induction of glutamine addiction[Together, these results suggest that this phenotype could be exploited as a cancer treatment through the use of GLOYTAMINOLYTIKWN enzyme inhibitors or treatment that cause a decrease in glutamine such as L-asparaginase.
In contrast, some types of cells show glutamine independence due to efrasis of GS such as glioma cells that can synthesize glutamine from glutamate through the activity of GS, maintaining cell proliferation during Glutamine deprivation [. Also, these cells use glucose as a TCA cycle-formulation source, which can adequately provide alpha-ketoglutarate for glutamate and glutamine synthesis. Alternatively, some types of cells can be adapted to the glutamine withdrawal using Asparaginine which is synthesized from glutamine. How cancer cells adapt their metabolic needs during glutamine deprivation remains to be clarified.
Glutamine Metabolism and mTORC1 pathway
The metabolism of glutamine and path mTORC1 have a close connection through various mechanisms. Glutamate induces mTORC1 and inhibits autoophygia by promoting cell growth {glutamate-mTORC1 axis in cancer development}.
The connection between the metabolism of glutamine and mTORC1 presents additional branches of connection, as Glutamine also plays a role in the rehabilitation of mTORC1 caused by autophagism, thus, the recycling of glutamine, supported From Autophaggia, it is sufficient to reactivate mTORC1 under restrictive conditions.
However, and paradoxically, long-term glutamate activation during nutrient containment causes an unbalanced activation of mTORC1 during nutrient deprivation and promotes apoptosis[ 92 ]. This type of cell death caused by metabolism is called “glutamate”, which supports the role of the tumour inhibitor of glutamine and mTORC1 metabolism (normally known as pre-proliferated inducers) during the Duration of the nutritional imbalance. During gloytamóptwsis, the inhibition of autophagtism mediated by mTORC1 leads to the accumulation of autophagtic protein that interacts with Caspase 8 and activates apoptosis.
In contrast, mTORC1 can regulate glutamine metabolism {enzymes GLS and GDH are regulated by mTORC1} and glutamine flow through glutamine carriers activates mTOR signaling [
In summary, glutamine uptake and metabolism have a close connection to mTOR signaling. As both pathways are regulated upwards in many cancers, strategies targeting both the metabolism of glutamine and signaling mTORC1 have shown synergistic effects.
Therapeutic applications
Given the dependence of cancer cells on the metabolism of glutamine, targeted treatments have been developed against the metabolism of glutamine, from the uptake of glutamine to enzymes catalyted with glutamine. Inhibition of GLS made attention due to the dysfunction of the GLS in a variety of cancers.
In addition to GLS inhibitors, strategies aimed at converting glutamate to alpha-ketoglutarate, such as GDH inhibitors and aminotransferase inhibitors, have also been evaluated in preclinical models of breast cancer and neuroblastoma
However, most of the anastoleis compounds are still in the pre-clinical evaluation stage or have been rejected directly due to high cytotoxicity.
In addition, some limitations have been reported resulting from the endurance of treatment in targeted treatments against glutamine metabolism, while the combined treatment of glutamine metabolism inhibitors and other road inhibitors caused Stronger declining response and enhanced anticancer efficacy. For example, inhibition of mTOR in polymorphistic glioblastoma cell lines led to a compensatory adjustment upwards of glutamine metabolism, promoting the resistance of the mTOR inhibitor. Thus, the combined inhibition of mTOR and GLS resulted in synergistic death of cell death and suspension of growth in mice models.
The primary substitute source in the developing cells is glutamine or which is the most abundant free amino acid in the blood and a naturally occurring source of carbon and nitrogen for the proliferation of cancer cells. Glutamine uptake is increased especially in cancer cells that have maladjusted oncogenes and tumour suppressor { C-my} c.
Glutamine is converted to {glutinolysis} in glutamic acid {from GLS} and finally to a-ketoglutarate which enters the TCA cycle to reconstitute the mass of mitochondrial citrate
Glutamine can be synthesized by cells via GLUL/glutamine Synthynine (GS) which catalyzes the condensation reaction between glutamate and ammonia in a way dependent by ATP and produces glutamine. The GS is mainly expressed in the liver, brain and muscles. GS has been found to be an index of hepatococytic carcinoma (HCC) and increased expression is associated with poor survival in glioblastoma.
Carbon
The incorporation of carbon from glutamine into the TCA cycle is essential for the bioenergetic needs and biosynthetic precursors of cells. A-ketoglutarate from glutamine can cause fatty acid synthesis through Isocellular dehydrogenase (IDH). IDH catalyzes the oxidative decarboxylation of isocellular salt for the production of α-ketoglutarate.
Nitrogen donor
Glutamine {has two atoms nitrogen, a and C-nitrogen} acts as a nitrogen donor and is used in the production of Uracil, Thyine, Cysein, adenine and guanine. Interestingly, only the C-nitrogen of glutamine is used for the synthesis of nucleotide.
Glutamine is the source of at least 50% of non-essential amino acids used in the synthesis of proteins from cancer cells. .
During ontogenesis, cancer cells continually face oxidative stress and in order to maintain oxidative homeostasis, cells need to increase their antioxidant ability with the metabolism of glutamine to play an important role in the antioxidant mechanisms. Glutamate derived from glutamine is used in the synthesis of glutathione (glutathione Synthethonis) and glutamine deprivation decreases the glutathione concentration of transformed cells . Glutamine oxidation supports the redox homeostasis WITH NADPH production which is used not only for lipid synthesis, but for the reduction of oxidized glutathione (GSSG), protecting cells from oxidative stress
Chromatin
The metabolism of glutamine not only produces building blocks and energy for cell growth, but it produces substrates for waterfalls that regulate the organization of chromatin. A-ketoglutarate derived from Glutamine is a Co-substrate of dixygenase enzymes to regulate hisone and methylation of DNA. Therefore, the metabolism of glutamine plays a role in gene expression through the contribution of α-ketoglutarate and electrical salt to the modification of the chromatin structure.
Cancer addiction to Glutamine
Due to the high demand for cancer cells for glutamine, the metabolism of glutamine is largely regulated in order to maintain cellular biosynthesis and cellular growth.
The first mechanism to enhance glutamine acquisition is to induce glutamine uptake. Different glutamine carriers contribute to glutamine uptake
And the potency of GLOYTAMINOLYTIKWN enzymes, GLS and GDH, are also regulated strictly.
When the level of extracellular glutamine is limited, some cancerous cell lines are capable of inducing GS expression in order to escape from cell death caused by glutamine deficiency. The GS was found to be hyperexpressed in certain types of cancer, such as breast cancer or glioblastoma, promoting cell proliferation the transcription of GS is activated with different oncology pathways, such as PI3K-PKB-FOXO, C-Myc and Yap1/Hippo[
Glutamine addiction occurs when cancer cells undergo cell death in conditions of glutamine restriction or when the metabolism of glutamine is inhibited. Many tumor cells which rely on glutamine catabolism to build blocks and energy have been reported to be addicted to glutamine. Glutamine-dependent cells are experiencing decreased survival or are still subjected to a deptotic cell death, associated with increased DNA damage, overproduction of ROS or reduced ratio of reduced/oxidized glutathione (GSH/GSSG). In this context, the onparent transcriptional factor C-Myc plays a key role in the induction of glutamine addiction[Together, these results suggest that this phenotype could be exploited as a cancer treatment through the use of GLOYTAMINOLYTIKWN enzyme inhibitors or treatment that cause a decrease in glutamine such as L-asparaginase.
In contrast, some types of cells show glutamine independence due to efrasis of GS such as glioma cells that can synthesize glutamine from glutamate through the activity of GS, maintaining cell proliferation during Glutamine deprivation [. Also, these cells use glucose as a TCA cycle-formulation source, which can adequately provide alpha-ketoglutarate for glutamate and glutamine synthesis. Alternatively, some types of cells can be adapted to the glutamine withdrawal using Asparaginine which is synthesized from glutamine. How cancer cells adapt their metabolic needs during glutamine deprivation remains to be clarified.
Glutamine Metabolism and mTORC1 pathway
The metabolism of glutamine and path mTORC1 have a close connection through various mechanisms. Glutamate induces mTORC1 and inhibits autoophygia by promoting cell growth {glutamate-mTORC1 axis in cancer development}.
The connection between the metabolism of glutamine and mTORC1 presents additional branches of connection, as Glutamine also plays a role in the rehabilitation of mTORC1 caused by autophagism, thus, the recycling of glutamine, supported From Autophaggia, it is sufficient to reactivate mTORC1 under restrictive conditions.
However, and paradoxically, long-term glutamate activation during nutrient containment causes an unbalanced activation of mTORC1 during nutrient deprivation and promotes apoptosis[ 92 ]. This type of cell death caused by metabolism is called “glutamate”, which supports the role of the tumour inhibitor of glutamine and mTORC1 metabolism (normally known as pre-proliferated inducers) during the Duration of the nutritional imbalance. During gloytamóptwsis, the inhibition of autophagtism mediated by mTORC1 leads to the accumulation of autophagtic protein that interacts with Caspase 8 and activates apoptosis.
In contrast, mTORC1 can regulate glutamine metabolism {enzymes GLS and GDH are regulated by mTORC1} and glutamine flow through glutamine carriers activates mTOR signaling [
In summary, glutamine uptake and metabolism have a close connection to mTOR signaling. As both pathways are regulated upwards in many cancers, strategies targeting both the metabolism of glutamine and signaling mTORC1 have shown synergistic effects.
Therapeutic applications
Given the dependence of cancer cells on the metabolism of glutamine, targeted treatments have been developed against the metabolism of glutamine, from the uptake of glutamine to enzymes catalyted with glutamine. Inhibition of GLS made attention due to the dysfunction of the GLS in a variety of cancers.
In addition to GLS inhibitors, strategies aimed at converting glutamate to alpha-ketoglutarate, such as GDH inhibitors and aminotransferase inhibitors, have also been evaluated in preclinical models of breast cancer and neuroblastoma
However, most of the anastoleis compounds are still in the pre-clinical evaluation stage or have been rejected directly due to high cytotoxicity.
In addition, some limitations have been reported resulting from the endurance of treatment in targeted treatments against glutamine metabolism, while the combined treatment of glutamine metabolism inhibitors and other road inhibitors caused Stronger declining response and enhanced anticancer efficacy. For example, inhibition of mTOR in polymorphistic glioblastoma cell lines led to a compensatory adjustment upwards of glutamine metabolism, promoting the resistance of the mTOR inhibitor. Thus, the combined inhibition of mTOR and GLS resulted in synergistic death of cell death and suspension of growth in mice models.
SOURCE: Cancer Resistance Drug 2018 { Institute of Chemistry and Biology, University of Bordeaux, France.
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