Abstract 1120: α-Tocopherol protects cells from lipid peroxidation and rescues tumorigenic phenotypes in CS/CSL patients with germline SDHx variants

Abstract Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid, and other cancers. Germline mutations in phosphatase and tensin homolog (PTEN) have been found in 25% of classic CS individuals accrued from the community. Additionally, we have shown that germline variations in succinate dehydrogenase genes (SDHx) occur in 8% of 608 PTEN mutation-negative CS and CS-like (CSL) individuals (SDHvar+), compared to 0/700 controls (p<0.0001, Fisher's 2-tailed exact test). SDHx genes encode for mitochondrial complex II which lies at the crossroads of electron transport and the tricarboxylic acid cycle. We previously showed that SDHx variants result in elevated reactive oxygen species (ROS) and in disruption of such mitochondrial metabolites as flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NAD) equilibrium in CS/CSL patient-derived lymphoblastoid cells. Consequently, improper NADH quinone oxidoreductase 1 (NQO1)-p53 interaction results in destabilization of p53 and apoptosis resistance. Here we further demonstrate that elevated ROS production results in higher lipid peroxidation in SDHvar+ cells compared to healthy control cells. This increased oxidative stress led to increased mutation accumulation in mitochondrial hypervariable region II (HVRII) in samples with SDHx variants compared to controls. Interestingly, α-tocopherol treatment, but not other antioxidants, can rescue SDHvar+ cells from apoptosis resistance. This lipid soluble vitamin E, functions as a peroxyl-radical scavenger, protecting SDHvar+ cells from oxidative damage. We observed down regulated lipid peroxidation in SDHvar+ cells after α-tocopherol exposure, as well as recovered p53 expression and FAD/NAD levels. We conclude that α-tocopherol selectively protects SDHvar+ cells from redox stress and downstream tumorigenic reprogramming, which may have intriguing clinical implications such as using vitamin E as a potential preventive adjunct for CS/CSL individuals with SDHx variants. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1120. doi:1538-7445.AM2012-1120