A Role for Cytosolic Fumarate Hydratase in Urea Cycle Metabolism and Renal Neoplasia

被引：76

作者：

Adam, Julie ^{[1
]}

Yang, Ming ^{[1
]}

Bauerschmidt, Christina ^{[1
]}

Kitagawa, Mitsuhiro ^{[4
]}

O'Flaherty, Linda ^{[1
]}

Maheswaran, Pratheesh ^{[1
]}

Oezkan, Gizem ^{[1
]}

Sahgal, Natasha ^{[6
]}

Baban, Dilair ^{[6
]}

Kato, Keiko ^{[4
]}

Saito, Kaori ^{[4
]}

Iino, Keiko ^{[4
]}

Igarashi, Kaori ^{[4
]}

Stratford, Michael ^{[8
]}

Pugh, Christopher ^{[2
]}

Tennant, Daniel A. ^{[9
]}

Ludwig, Christian ^{[9
]}

Davies, Benjamin ^{[7
]}

Ratcliffe, Peter J. ^{[2
]}

El-Bahrawy, Mona ^{[10
,11
]}

Ashrafian, Houman ^{[12
]}

Soga, Tomoyoshi ^{[4
,5
]}

Pollard, Patrick J. ^{[1
,3
]}

机构：

[1] Univ Oxford, Nuffield Dept Med, Canc Biol & Metab Grp, Oxford OX3 7BN, England

[2] Univ Oxford, Nuffield Dept Med, Hypoxia Biol Grp, Oxford OX3 7BN, England

[3] Univ Oxford, Nuffield Dept Med, Oxford Keio Metabol Consortium, Oxford OX3 7BN, England

[4] Keio Univ, Inst Adv Biosci, Tsuruoka, Yamagata 9970052, Japan

[5] Keio Univ, Oxford Keio Metabol Consortium, Tsuruoka, Yamagata 9970052, Japan

[6] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[7] Univ Oxford, Wellcome Trust Ctr Human Genet, Transgen Core, Oxford OX3 7BN, England

[8] Univ Oxford, Dept Oncol, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England

[9] Univ Birmingham, Coll Med & Dent Sci, Sch Canc Sci, Birmingham B15 2TT, W Midlands, England

[10] Univ London Imperial Coll Sci Technol & Med, Dept Histopathol, Hammersmith Hosp, London W12 0NN, England

[11] Univ Alexandria, Fac Med, Dept Pathol, Alexandria, Egypt

[12] Univ Oxford, Dept Cardiovasc Med, Oxford OX3 9DU, England

来源：

CELL REPORTS | 2013年 / 3卷 / 05期

基金：

欧洲研究理事会; 英国惠康基金;

关键词：

INTRATUMOR HETEROGENEITY; ARGININE DEPRIVATION; ALPHA-KETOGLUTARATE; EXPRESSION; CANCER; FH; THERAPY; TUMORS; GROWTH; DEHYDROGENASE;

D O I：

10.1016/j.celrep.2013.04.006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.

引用

页码：1440 / 1448

页数：9

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