Dietary Manipulation of Amino Acids for Cancer Therapy

Jiménez-Alonso, Julio José; López‐Lázaro, Miguel

doi:10.3390/nu15132879

Cited by 8 publications

(3 citation statements)

References 371 publications

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“…However, due mostly to reasons provided in Section 10.2. above, only perfunctory attention has been accorded the GTωA pathway (i.e., L-glutamine KGM → α-ketoglutarate). Several authors (e.g., [158][159][160][161]) have quoted our work that demonstrates GLS1 protein/activity is increased in aggressive prostate cancer cells (cf., [1]), but neglected to provide the rationale associated with the upregulation of the GTωA pathway in these cells. This omission resulted in providing only partial understanding of the integrative relationship between the GTωA and canonical pathways for conversion of L-glutamine to α-ketoglutarate, particularly in cancerous tissues.…”

Section: Possible Role Of Glutamate Dehydrogenase (Gdh) In the Produc...mentioning

confidence: 97%

Metabolic Heterogeneity, Plasticity and Adaptation to “Gluta-mine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase – ω-Amidase (Glutaminase II)] Pathway.

Cooper¹,

Dorai²,

Pinto³

et al. 2023

Preprint

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Many cancers utilize L-glutamine as a major energy source. This “L-glutamine addiction” involves a well-characterized pathway whereby L-glutamine is hydrolyzed by a glutaminase (GLS) to L-glutamate, which is then converted to α-ketoglutarate, the carbons of which enter the tricarboxylic acid (TCA) cycle. However, mammalian tissues/cancers possess a rarely mentioned alternative pathway (the glutaminase II pathway): L-Glutamine is transaminated to α-ketoglutaramate (KGM), followed by ω-amidase (ωA)-catalyzed hydrolysis of KGM to α-ketoglutarate. Uncertainty may prevail over the name glutaminase II which may be confused with the enzyme named glutaminase 2 (GLS2). Thus, we recently suggested a new name for the glutaminase II pathway, namely the glutamine transaminase-ω-amidase (GTωA) pathway. Herein, we 1) evaluate three recent articles that mention L-glutamine addiction, but not the GTωA pathway, 2) summarize the metabolic importance of the GTωA pathway, including its role in closing the methionine salvage pathway, and 3) as a source of anaplerotic α-ketoglutarate. An advantage of the GTωA pathway [i.e., L-glutamine + α-keto acid + H2O α-ketoglutarate + L-amino acid + +NH4] is that it is irreversible and that there is no net change in redox status, permitting α-ketoglutarate production during hypoxia. Finally, we discuss possible clinical benefits of GTωA pathway inhibitors.

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Section: Possible Role Of Glutamate Dehydrogenase (Gdh) In the Produc...mentioning

confidence: 97%

Metabolic Heterogeneity, Plasticity and Adaptation to “Gluta-mine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase – ω-Amidase (Glutaminase II)] Pathway.

Cooper¹,

Dorai²,

Pinto³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Dietary restriction of protein and certain amino acids, including serine, methionine, and branched-chain amino acids (BCAAs) such as leucine, isoleucine, and valine, has been shown to impede tumor growth. 159 One mechanism through which protein restriction may inhibit tumor growth is via the IGF-1 signaling pathway. In melanoma and breast cancer mouse models, it has been observed that mice fed a low-protein diet (4% kcal protein) exhibit reduced IGF-1 levels and slower tumor progression compared to those fed a high-protein diet (18% kcal protein).…”

Section: Targeted Dietary Interventions and Mechanistic Insights Into...mentioning

confidence: 99%

Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential

Xiao,

Gong,

et al. 2024

Sig Transduct Target Ther

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Diet, serving as a vital source of nutrients, exerts a profound influence on human health and disease progression. Recently, dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases, autoimmune diseases, cardiovascular diseases, and metabolic disorders. These interventions have demonstrated substantial potential in modulating metabolism, disease trajectory, and therapeutic responses. Metabolic reprogramming is a hallmark of malignant progression, and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer eradication. Dietary intake, as a key environmental factor, can influence tumor metabolism. Emerging evidence indicates that dietary interventions might affect the nutrient availability in tumors, thereby increasing the efficacy of cancer treatments. However, the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is complex. Despite encouraging results, the mechanisms underlying diet-based therapeutic strategies remain largely unexplored, often resulting in underutilization in disease management. In this review, we aim to illuminate the potential effects of various dietary interventions, including calorie restriction, fasting-mimicking diet, ketogenic diet, protein restriction diet, high-salt diet, high-fat diet, and high-fiber diet, on cancer and the aforementioned diseases. We explore the multifaceted impacts of these dietary interventions, encompassing their immunomodulatory effects, other biological impacts, and underlying molecular mechanisms. This review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management.

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“…above, only perfunctory attention has been accorded the GTωA pathway (i.e., l -glutamine ⇆ KGM → α-ketoglutarate). Several authors (e.g., [ 158 , 159 , 160 , 161 ]) have quoted our work that demonstrates GLS1 protein/activity is increased in aggressive prostate cancer cells (cf., [ 1 ]), but neglected to provide the rationale associated with the upregulation of the GTωA pathway in these cells. This omission resulted in providing only partial understanding of the integrative relationship between the GTωA and canonical pathways for conversion of l -glutamine to α-ketoglutarate, particularly in cancerous tissues.…”

Section: Glutaminase II (Gtωa) Pathway Enzymes In Cancermentioning

confidence: 99%

Metabolic Heterogeneity, Plasticity, and Adaptation to “Glutamine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase—ω-Amidase (Glutaminase II)] Pathway

Cooper

Dorai

Pinto

et al. 2023

Biology

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Many cancers utilize l-glutamine as a major energy source. Often cited in the literature as “l-glutamine addiction”, this well-characterized pathway involves hydrolysis of l-glutamine by a glutaminase to l-glutamate, followed by oxidative deamination, or transamination, to α-ketoglutarate, which enters the tricarboxylic acid cycle. However, mammalian tissues/cancers possess a rarely mentioned, alternative pathway (the glutaminase II pathway): l-glutamine is transaminated to α-ketoglutaramate (KGM), followed by ω-amidase (ωA)-catalyzed hydrolysis of KGM to α-ketoglutarate. The name glutaminase II may be confused with the glutaminase 2 (GLS2) isozyme. Thus, we recently renamed the glutaminase II pathway the “glutamine transaminase—ω-amidase (GTωA)” pathway. Herein, we summarize the metabolic importance of the GTωA pathway, including its role in closing the methionine salvage pathway, and as a source of anaplerotic α-ketoglutarate. An advantage of the GTωA pathway is that there is no net change in redox status, permitting α-ketoglutarate production during hypoxia, diminishing cellular energy demands. We suggest that the ability to coordinate control of both pathways bestows a metabolic advantage to cancer cells. Finally, we discuss possible benefits of GTωA pathway inhibitors, not only as aids to studying the normal biological roles of the pathway but also as possible useful anticancer agents.

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Dietary Manipulation of Amino Acids for Cancer Therapy

Cited by 8 publications

References 371 publications

Metabolic Heterogeneity, Plasticity and Adaptation to “Gluta-mine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase – ω-Amidase (Glutaminase II)] Pathway.

Metabolic Heterogeneity, Plasticity and Adaptation to “Gluta-mine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase – ω-Amidase (Glutaminase II)] Pathway.

Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential

Metabolic Heterogeneity, Plasticity, and Adaptation to “Glutamine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase—ω-Amidase (Glutaminase II)] Pathway

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