title: Vitamin E protects against lipid peroxidation and rescues tumorigenic phenotypes in cowden/cowden-like patient-derived lymphoblast cells with germline SDHx variants.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Cleveland Clinic Genomic Medicine Institute, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA.
authors: Ying
authors: Y
authors: Ni
authors: Charis
authors: C
authors: Eng
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics*; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010641:Phenotype; D011110:Polymorphism, Genetic; D013385:Succinate Dehydrogenase / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D016159:Tumor Suppressor Protein p53; D014810:Vitamin E; D013385:Succinate Dehydrogenase; D024502:alpha-Tocopherol