Glucose-independent glutamine-driven TCA cycle in cancer cells

Brad Poore, Nicholas Siegel, Joshua K. Park, Benjamin Jung Hwang, Iman Afif, Quy Hoa Le Thi

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Although genetic alterations are ultimately believed to cause cancer, they can also lead to dysregulation of genes encoding metabolic enzymes that enables cancer cells to proliferate and metastasize. Even though the tricarboxylic acid (TCA) cycle is considered an oxidation pathway for glucose metabolism, Le et al. have demonstrated otherwise. Using stable isotope-resolved metabolomics to resolve 13C and 15N from labeled glucose or glutamine, they found that B-cell cancers maintain their TCA cycle solely relying on glutamine when glucose is withdrawn. This glucose-independent TCA cycle allows cancer cells to maintain its bioenergetics, catabolic, and anabolic needs under glucose limited conditions. The effect is so profound that certain cancer cells become addicted and cannot proliferate without glutamine, even in the presence of glucose. Due to glutamine’s emerging role in cancer, targeting the glutaminolysis pathway is a promising new approach to cancer therapy. Moreover, the results of their research demonstrated that inhibition of glutaminase, an enzyme that converts glutamine to glutamate, slows B-cell cancer growth. The ability of B-cell cancer cells to reprogram their metabolism by using glutamine instead of glucose to adapt to the nutrient availability in the tumor microenvironment confers a selective advantage for cancer cell survival and proliferation. This knowledge gives researchers a critical means by which to exploit the metabolic adaptations of these cancer cells and develop new cancer therapies.

Original languageEnglish (US)
Title of host publicationGlutamine in Clinical Nutrition
PublisherSpringer New York
Pages77-85
Number of pages9
ISBN (Print)9781493919321, 9781493919314
DOIs
StatePublished - Jan 1 2015

Fingerprint

Citric Acid Cycle
tricarboxylic acid cycle
Glutamine
glutamine
Glucose
Cells
glucose
neoplasms
Neoplasms
B-lymphocytes
Metabolism
glutaminase
B-Lymphocytes
therapeutics
Enzymes
metabolism
metabolomics
Glutaminase
Enzyme inhibition
enzymes

Keywords

  • Glucose-deficient microenvironment
  • Glucose-independent glutamine-driven TCA cycle
  • Glutaminolysis
  • Targeting glutamine metabolism
  • TCA cycle

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Engineering(all)
  • Agricultural and Biological Sciences(all)

Cite this

Poore, B., Siegel, N., Park, J. K., Hwang, B. J., Afif, I., & Le Thi, Q. H. (2015). Glucose-independent glutamine-driven TCA cycle in cancer cells. In Glutamine in Clinical Nutrition (pp. 77-85). Springer New York. https://doi.org/10.1007/978-1-4939-1932-1_6

Glucose-independent glutamine-driven TCA cycle in cancer cells. / Poore, Brad; Siegel, Nicholas; Park, Joshua K.; Hwang, Benjamin Jung; Afif, Iman; Le Thi, Quy Hoa.

Glutamine in Clinical Nutrition. Springer New York, 2015. p. 77-85.

Research output: Chapter in Book/Report/Conference proceedingChapter

Poore, B, Siegel, N, Park, JK, Hwang, BJ, Afif, I & Le Thi, QH 2015, Glucose-independent glutamine-driven TCA cycle in cancer cells. in Glutamine in Clinical Nutrition. Springer New York, pp. 77-85. https://doi.org/10.1007/978-1-4939-1932-1_6
Poore B, Siegel N, Park JK, Hwang BJ, Afif I, Le Thi QH. Glucose-independent glutamine-driven TCA cycle in cancer cells. In Glutamine in Clinical Nutrition. Springer New York. 2015. p. 77-85 https://doi.org/10.1007/978-1-4939-1932-1_6
Poore, Brad ; Siegel, Nicholas ; Park, Joshua K. ; Hwang, Benjamin Jung ; Afif, Iman ; Le Thi, Quy Hoa. / Glucose-independent glutamine-driven TCA cycle in cancer cells. Glutamine in Clinical Nutrition. Springer New York, 2015. pp. 77-85
@inbook{5af712e53fa14777bf89f46bc79be0ba,
title = "Glucose-independent glutamine-driven TCA cycle in cancer cells",
abstract = "Although genetic alterations are ultimately believed to cause cancer, they can also lead to dysregulation of genes encoding metabolic enzymes that enables cancer cells to proliferate and metastasize. Even though the tricarboxylic acid (TCA) cycle is considered an oxidation pathway for glucose metabolism, Le et al. have demonstrated otherwise. Using stable isotope-resolved metabolomics to resolve 13C and 15N from labeled glucose or glutamine, they found that B-cell cancers maintain their TCA cycle solely relying on glutamine when glucose is withdrawn. This glucose-independent TCA cycle allows cancer cells to maintain its bioenergetics, catabolic, and anabolic needs under glucose limited conditions. The effect is so profound that certain cancer cells become addicted and cannot proliferate without glutamine, even in the presence of glucose. Due to glutamine’s emerging role in cancer, targeting the glutaminolysis pathway is a promising new approach to cancer therapy. Moreover, the results of their research demonstrated that inhibition of glutaminase, an enzyme that converts glutamine to glutamate, slows B-cell cancer growth. The ability of B-cell cancer cells to reprogram their metabolism by using glutamine instead of glucose to adapt to the nutrient availability in the tumor microenvironment confers a selective advantage for cancer cell survival and proliferation. This knowledge gives researchers a critical means by which to exploit the metabolic adaptations of these cancer cells and develop new cancer therapies.",
keywords = "Glucose-deficient microenvironment, Glucose-independent glutamine-driven TCA cycle, Glutaminolysis, Targeting glutamine metabolism, TCA cycle",
author = "Brad Poore and Nicholas Siegel and Park, {Joshua K.} and Hwang, {Benjamin Jung} and Iman Afif and {Le Thi}, {Quy Hoa}",
year = "2015",
month = "1",
day = "1",
doi = "10.1007/978-1-4939-1932-1_6",
language = "English (US)",
isbn = "9781493919321",
pages = "77--85",
booktitle = "Glutamine in Clinical Nutrition",
publisher = "Springer New York",

}

TY - CHAP

T1 - Glucose-independent glutamine-driven TCA cycle in cancer cells

AU - Poore, Brad

AU - Siegel, Nicholas

AU - Park, Joshua K.

AU - Hwang, Benjamin Jung

AU - Afif, Iman

AU - Le Thi, Quy Hoa

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Although genetic alterations are ultimately believed to cause cancer, they can also lead to dysregulation of genes encoding metabolic enzymes that enables cancer cells to proliferate and metastasize. Even though the tricarboxylic acid (TCA) cycle is considered an oxidation pathway for glucose metabolism, Le et al. have demonstrated otherwise. Using stable isotope-resolved metabolomics to resolve 13C and 15N from labeled glucose or glutamine, they found that B-cell cancers maintain their TCA cycle solely relying on glutamine when glucose is withdrawn. This glucose-independent TCA cycle allows cancer cells to maintain its bioenergetics, catabolic, and anabolic needs under glucose limited conditions. The effect is so profound that certain cancer cells become addicted and cannot proliferate without glutamine, even in the presence of glucose. Due to glutamine’s emerging role in cancer, targeting the glutaminolysis pathway is a promising new approach to cancer therapy. Moreover, the results of their research demonstrated that inhibition of glutaminase, an enzyme that converts glutamine to glutamate, slows B-cell cancer growth. The ability of B-cell cancer cells to reprogram their metabolism by using glutamine instead of glucose to adapt to the nutrient availability in the tumor microenvironment confers a selective advantage for cancer cell survival and proliferation. This knowledge gives researchers a critical means by which to exploit the metabolic adaptations of these cancer cells and develop new cancer therapies.

AB - Although genetic alterations are ultimately believed to cause cancer, they can also lead to dysregulation of genes encoding metabolic enzymes that enables cancer cells to proliferate and metastasize. Even though the tricarboxylic acid (TCA) cycle is considered an oxidation pathway for glucose metabolism, Le et al. have demonstrated otherwise. Using stable isotope-resolved metabolomics to resolve 13C and 15N from labeled glucose or glutamine, they found that B-cell cancers maintain their TCA cycle solely relying on glutamine when glucose is withdrawn. This glucose-independent TCA cycle allows cancer cells to maintain its bioenergetics, catabolic, and anabolic needs under glucose limited conditions. The effect is so profound that certain cancer cells become addicted and cannot proliferate without glutamine, even in the presence of glucose. Due to glutamine’s emerging role in cancer, targeting the glutaminolysis pathway is a promising new approach to cancer therapy. Moreover, the results of their research demonstrated that inhibition of glutaminase, an enzyme that converts glutamine to glutamate, slows B-cell cancer growth. The ability of B-cell cancer cells to reprogram their metabolism by using glutamine instead of glucose to adapt to the nutrient availability in the tumor microenvironment confers a selective advantage for cancer cell survival and proliferation. This knowledge gives researchers a critical means by which to exploit the metabolic adaptations of these cancer cells and develop new cancer therapies.

KW - Glucose-deficient microenvironment

KW - Glucose-independent glutamine-driven TCA cycle

KW - Glutaminolysis

KW - Targeting glutamine metabolism

KW - TCA cycle

UR - http://www.scopus.com/inward/record.url?scp=84944571853&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84944571853&partnerID=8YFLogxK

U2 - 10.1007/978-1-4939-1932-1_6

DO - 10.1007/978-1-4939-1932-1_6

M3 - Chapter

AN - SCOPUS:84944571853

SN - 9781493919321

SN - 9781493919314

SP - 77

EP - 85

BT - Glutamine in Clinical Nutrition

PB - Springer New York

ER -