A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2013-05-01
Date Acceptance
2013-04-08
Citation
Cell Reports, 2013, 3 (5), pp.1440-1448
ISSN
2211-1247
Publisher
Elsevier
Start Page
1440
End Page
1448
Journal / Book Title
Cell Reports
Volume
3
Issue
5
Copyright Statement
© 2013 The Authors. Published by Elsevier Inc. This is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution,
and reproduction in any medium, provided the original author and source
are credited.
Commons Attribution License, which permits unrestricted use, distribution,
and reproduction in any medium, provided the original author and source
are credited.
License URL
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000321899300015&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell Biology
INTRATUMOR HETEROGENEITY
ARGININE DEPRIVATION
ALPHA-KETOGLUTARATE
EXPRESSION
CANCER
FH
THERAPY
TUMORS
GROWTH
DEHYDROGENASE
Publication Status
Published
Date Publish Online
2013-05-02