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).
| Language | English |
|---|---|
| Article number | 12 |
| Number of pages | 11 |
| Journal | Cancer and Metabolism |
| Volume | 1 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2013 |
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Keywords
- fumarate hydratase-deficient
- cancer cells
- reversed argininosuccinate lyase activity
Cite this
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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 journal › Article
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
M1 - 12
ER -