Document Detail

Vitamin E protects against lipid peroxidation and rescues tumorigenic phenotypes in cowden/cowden-like patient-derived lymphoblast cells with germline SDHx variants.
MedLine Citation:
PMID:  22829200     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid, and other cancers. Germline variations in succinate dehydrogenase genes (SDHx) occur in approximately 10% PTEN mutation-negative CS and CS-like (CSL) individuals (SDH(var+)). We previously showed that SDHx variants result in elevated reactive oxygen species (ROS), disruption of nicotinamide adenine dinucleotide (NAD) equilibrium, and destabilization of p53 hence apoptosis resistance in CS/CSL patient-derived lymphoblastoid cells. In the present study, we sought to address the tumorigenic impacts of increased ROS and the potential of protecting SDH(var+) cells with antioxidants.
EXPERIMENTAL DESIGN: We measured the lipid peroxidation levels in patient-derived SDH(var+) lymphoblastoid cells and sequenced 74 controls or SDH(var+) germline DNA samples for mitochondrial hypervariable region II (HVRII) polymorphisms. SDH(var+) lymphoblastoid cells were treated with various antioxidants to check p53 expression and sub-G(1) cell population with cell-cycle analysis.
RESULTS: We showed that elevated ROS results in higher lipid peroxidation in SDH(var+) cells. Accumulation of polymorphisms in mitochondrial HVRII was observed in SDH(var+) samples. Interestingly, α-tocopherol (vitamin E) treatment, but not other antioxidants, rescued SDH(var+) cells from apoptosis resistance and protected SDH(var+) cells from oxidative damage such as decreased lipid peroxidation as well as partially recovered p53 expression and NAD/NADH levels.
CONCLUSIONS: We conclude that disruption of complex II because of SDHx variants leads to increased ROS generation, specifically accompanied by lipid peroxidation. The lipid soluble antioxidant α-tocopherol can selectively protect SDH(var+) cells from oxidative damage, apoptosis resistance, and rebalance redox metabolites NAD/NADH.
Ying Ni; Charis Eng
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-24
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  18     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-18     Completed Date:  2013-03-22     Revised Date:  2013-09-18    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4954-61     Citation Subset:  IM    
Copyright Information:
©2012 AACR.
Cleveland Clinic Genomic Medicine Institute, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA.
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MeSH Terms
Antioxidants / pharmacology
Apoptosis / drug effects,  genetics
Cell Line, Transformed
Cell Transformation, Neoplastic / drug effects*,  genetics*
Germ-Line Mutation*
Hamartoma Syndrome, Multiple / genetics*,  metabolism
Lipid Peroxidation / drug effects*,  genetics
Mitochondria / genetics,  metabolism
Oxidation-Reduction / drug effects
Polymorphism, Genetic
Succinate Dehydrogenase / genetics*
Tumor Suppressor Protein p53 / genetics,  metabolism
Vitamin E / pharmacology*
alpha-Tocopherol / pharmacology
Grant Support
Reg. No./Substance:
0/Antioxidants; 0/Tumor Suppressor Protein p53; 1406-18-4/Vitamin E; 59-02-9/alpha-Tocopherol; EC Dehydrogenase

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