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Molecular Pathways: Fumarate Hydratase-Deficient Kidney Cancer: Targeting the Warburg Effect in Cancer.
MedLine Citation:
PMID:  23633457     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for development of cutaneous and uterine leiomyomas and an aggressive form of type II papillary kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid cycle (TCA) enzyme, fumarate hydratase (FH). FH-deficient kidney cancer is characterized by impaired oxidative phosphorylation and a metabolic shift to aerobic glycolysis, a form of metabolic reprogramming known as the Warburg effect. Increased glycolysis generates ATP needed for increased cell proliferation. Levels of the cellular energy sensor, AMPK, are decreased in FH-deficient kidney cancer; resulting in diminished p53 levels and decreased expression of the iron importer, DMT1, leading to low cellular iron levels and enhanced fatty acid synthesis by diminishing phosphorylation of acetyl CoA carboxylase, a rate limiting step for fatty acid synthesis. Increased fumarate and decreased iron levels in FH-deficient kidney cancer cells inactivate prolyl hydroxylases, leading to stabilization of HIF1α, and increased expression of genes such as vascular endothelial growth factor (VEGF) and GLUT1 to provide fuel needed for rapid growth demands. Therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials. These same types of metabolic shifts have been found in a wide variety of other cancer types. Targeting the metabolic basis of a rare cancer such as FH-deficient kidney cancer will hopefully provide the foundation for the development of effective forms of therapies for other, more common cancers.
Authors:
W Marston Linehan; Tracy A Rouault
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-5-1
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  -     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-5-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health.
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