Document Detail


Glucose Oxidation Modulates Anoikis and Tumor Metastasis.
MedLine Citation:
PMID:  22431524     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Cancer cells exhibit altered glucose metabolism characterized by a preference for aerobic glycolysis or the Warburg effect, and resist matrix detachment-induced apoptosis called "anoikis", a barrier to metastasis. It remains largely unclear whether tumor metabolism influences anoikis and metastasis. Here we show when detached from matrix, untransformed mammary epithelial cells undergo metabolic reprogramming by markedly upregulating pyruvate dehydrogenase (PDH) kinase (PDK) 4 through estrogen-related receptor gamma (ERRγ), thereby inhibiting PDH and attenuating the flux of glycolytic carbon into mitochondrial oxidation. To decipher the significance of this metabolic response, we found that depletion of PDK4 or activation of PDH increases mitochondrial respiration and oxidative stress in suspended cells, resulting in heightened anoikis. Conversely, overexpression of PDKs prolongs survival of cells in suspension. Therefore, decreased glucose oxidation following cell detachment confers anoikis resistance. Unlike untransformed cells, most cancer cells demonstrate reduced glucose oxidation even under attached conditions, and thus inherently possess survival advantage when suspended. Normalization of glucose metabolism by stimulating PDH in cancer cells restores their susceptibility to anoikis and impairs their metastatic potential. These results suggest that the Warburg effect, more specifically the diminished glucose oxidation, promotes anoikis resistance and metastasis, and that PDKs are potential targets for anti-metastasis therapy.
Authors:
Sushama Kamarajugadda; Lauren Stemboroski; Qingsong Cai; Nicholas E Simpson; Sushrusha Nayak; Ming Tan; Jianrong Lu
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-19
Journal Detail:
Title:  Molecular and cellular biology     Volume:  -     ISSN:  1098-5549     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Departments of Biochemistry and Molecular Biology.
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