Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells

Liang Zheng, Elaine D Mackenzie, Saadia A Karim, Ann Hedley, Karen Blyth, Gabriela Kalna, David G Watson, Peter Szlosarek, Christian Frezza, Eyal Gottlieb

Research output: Contribution to journalArticle

Abstract

Loss of function of fumarate hydratase (FH), the mitochondrial tumor suppressor and tricarboxylic acid (TCA) cycle enzyme, is associated with a highly malignant form of papillary and collecting duct renal cell cancer. The accumulation of fumarate in these cells has been linked to the tumorigenic process. However, little is known about the overall effects of the loss of FH on cellular metabolism.
We performed comprehensive metabolomic analyses of urine from Fh1-deficient mice and stable isotopologue tracing from human and mouse FH-deficient cell lines to investigate the biochemical signature of the loss of FH.
The metabolomics analysis revealed that the urea cycle metabolite argininosuccinate is a common metabolic biomarker of FH deficiency. Argininosuccinate was found to be produced from arginine and fumarate by the reverse activity of the urea cycle enzyme argininosuccinate lyase (ASL), making these cells auxotrophic for arginine. Depleting arginine from the growth media by the addition of pegylated arginine deiminase (ADI-PEG 20) decreased the production of argininosuccinate in FH-deficient cells and reduced cell survival and proliferation.
These results unravel a previously unidentified correlation between fumarate accumulation and the urea cycle enzyme ASL in FH-deficient cells. The finding that FH-deficient cells become auxotrophic for arginine opens a new therapeutic perspective for the cure of hereditary leiomyomatosis and renal cell cancer (HLRCC).

LanguageEnglish
Article number12
Number of pages11
JournalCancer and Metabolism
Volume1
Issue number1
DOIs
Publication statusPublished - 2013

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Argininosuccinate Lyase
Fumarate Hydratase
Cells
Fumarates
Arginine
Neoplasms
Urea
Metabolomics
Enzymes
Activity Cycles
Citric Acid Cycle
Renal Cell Carcinoma
Biomarkers
Metabolites
Metabolism
Cell Survival
Ducts
Polyethylene glycols
Tumors
Cell Proliferation

Keywords

  • fumarate hydratase-deficient
  • cancer cells
  • reversed argininosuccinate lyase activity

Cite this

Zheng, L., Mackenzie, E. D., Karim, S. A., Hedley, A., Blyth, K., Kalna, G., ... Gottlieb, E. (2013). Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells. Cancer and Metabolism, 1(1), [12]. https://doi.org/10.1186/2049-3002-1-12
Zheng, Liang ; Mackenzie, Elaine D ; Karim, Saadia A ; Hedley, Ann ; Blyth, Karen ; Kalna, Gabriela ; Watson, David G ; Szlosarek, Peter ; Frezza, Christian ; Gottlieb, Eyal. / Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells. In: Cancer and Metabolism. 2013 ; Vol. 1, No. 1.
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abstract = "Loss of function of fumarate hydratase (FH), the mitochondrial tumor suppressor and tricarboxylic acid (TCA) cycle enzyme, is associated with a highly malignant form of papillary and collecting duct renal cell cancer. The accumulation of fumarate in these cells has been linked to the tumorigenic process. However, little is known about the overall effects of the loss of FH on cellular metabolism.We performed comprehensive metabolomic analyses of urine from Fh1-deficient mice and stable isotopologue tracing from human and mouse FH-deficient cell lines to investigate the biochemical signature of the loss of FH.The metabolomics analysis revealed that the urea cycle metabolite argininosuccinate is a common metabolic biomarker of FH deficiency. Argininosuccinate was found to be produced from arginine and fumarate by the reverse activity of the urea cycle enzyme argininosuccinate lyase (ASL), making these cells auxotrophic for arginine. Depleting arginine from the growth media by the addition of pegylated arginine deiminase (ADI-PEG 20) decreased the production of argininosuccinate in FH-deficient cells and reduced cell survival and proliferation.These results unravel a previously unidentified correlation between fumarate accumulation and the urea cycle enzyme ASL in FH-deficient cells. The finding that FH-deficient cells become auxotrophic for arginine opens a new therapeutic perspective for the cure of hereditary leiomyomatosis and renal cell cancer (HLRCC).",
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Zheng, L, Mackenzie, ED, Karim, SA, Hedley, A, Blyth, K, Kalna, G, Watson, DG, Szlosarek, P, Frezza, C & Gottlieb, E 2013, 'Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells' Cancer and Metabolism, vol. 1, no. 1, 12. https://doi.org/10.1186/2049-3002-1-12

Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells. / Zheng, Liang; Mackenzie, Elaine D; Karim, Saadia A; Hedley, Ann; Blyth, Karen; Kalna, Gabriela; Watson, David G; Szlosarek, Peter; Frezza, Christian; Gottlieb, Eyal.

In: Cancer and Metabolism, Vol. 1, No. 1, 12, 2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells

AU - Zheng, Liang

AU - Mackenzie, Elaine D

AU - Karim, Saadia A

AU - Hedley, Ann

AU - Blyth, Karen

AU - Kalna, Gabriela

AU - Watson, David G

AU - Szlosarek, Peter

AU - Frezza, Christian

AU - Gottlieb, Eyal

PY - 2013

Y1 - 2013

N2 - Loss of function of fumarate hydratase (FH), the mitochondrial tumor suppressor and tricarboxylic acid (TCA) cycle enzyme, is associated with a highly malignant form of papillary and collecting duct renal cell cancer. The accumulation of fumarate in these cells has been linked to the tumorigenic process. However, little is known about the overall effects of the loss of FH on cellular metabolism.We performed comprehensive metabolomic analyses of urine from Fh1-deficient mice and stable isotopologue tracing from human and mouse FH-deficient cell lines to investigate the biochemical signature of the loss of FH.The metabolomics analysis revealed that the urea cycle metabolite argininosuccinate is a common metabolic biomarker of FH deficiency. Argininosuccinate was found to be produced from arginine and fumarate by the reverse activity of the urea cycle enzyme argininosuccinate lyase (ASL), making these cells auxotrophic for arginine. Depleting arginine from the growth media by the addition of pegylated arginine deiminase (ADI-PEG 20) decreased the production of argininosuccinate in FH-deficient cells and reduced cell survival and proliferation.These results unravel a previously unidentified correlation between fumarate accumulation and the urea cycle enzyme ASL in FH-deficient cells. The finding that FH-deficient cells become auxotrophic for arginine opens a new therapeutic perspective for the cure of hereditary leiomyomatosis and renal cell cancer (HLRCC).

AB - Loss of function of fumarate hydratase (FH), the mitochondrial tumor suppressor and tricarboxylic acid (TCA) cycle enzyme, is associated with a highly malignant form of papillary and collecting duct renal cell cancer. The accumulation of fumarate in these cells has been linked to the tumorigenic process. However, little is known about the overall effects of the loss of FH on cellular metabolism.We performed comprehensive metabolomic analyses of urine from Fh1-deficient mice and stable isotopologue tracing from human and mouse FH-deficient cell lines to investigate the biochemical signature of the loss of FH.The metabolomics analysis revealed that the urea cycle metabolite argininosuccinate is a common metabolic biomarker of FH deficiency. Argininosuccinate was found to be produced from arginine and fumarate by the reverse activity of the urea cycle enzyme argininosuccinate lyase (ASL), making these cells auxotrophic for arginine. Depleting arginine from the growth media by the addition of pegylated arginine deiminase (ADI-PEG 20) decreased the production of argininosuccinate in FH-deficient cells and reduced cell survival and proliferation.These results unravel a previously unidentified correlation between fumarate accumulation and the urea cycle enzyme ASL in FH-deficient cells. The finding that FH-deficient cells become auxotrophic for arginine opens a new therapeutic perspective for the cure of hereditary leiomyomatosis and renal cell cancer (HLRCC).

KW - fumarate hydratase-deficient

KW - cancer cells

KW - reversed argininosuccinate lyase activity

UR - http://www.cancerandmetabolism.com/

U2 - 10.1186/2049-3002-1-12

DO - 10.1186/2049-3002-1-12

M3 - Article

VL - 1

JO - Cancer and Metabolism

T2 - Cancer and Metabolism

JF - Cancer and Metabolism

SN - 2049-3002

IS - 1

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ER -