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Clin Cancer Res. 2012 Sep 15;18(18):4954-61. Epub 2012 Jul 24.

Vitamin E protects against lipid peroxidation and rescues tumorigenic phenotypes in cowden/cowden-like patient-derived lymphoblast cells with germline SDHx variants.

Author information

1
Cleveland Clinic Genomic Medicine Institute, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA.

Abstract

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.

PMID:
22829200
PMCID:
PMC3445717
DOI:
10.1158/1078-0432.CCR-12-1055
[Indexed for MEDLINE]
Free PMC Article

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