Glutathione S-transferasesP1 AA (105Ile) allele increases oral cancer risk, interacts strongly with c-Jun Kinase and weakly detoxifies areca-nut metabolites

The Glutathione S-transferases (GSTs) protects cellular DNA against oxidative damage. The role of GSTP1 polymorphism (A313G; Ile105Val) as a susceptibility factor in oral cancer was evaluated in a hospital-based case-control study in North-East India, because the habit of chewing raw areca-nut (RAN) with/without tobacco is common in this region. Genetic polymorphism was investigated by genotyping 445 cases and 444 controls. Individuals with the GSTP1 AA-genotype showed association with the oral cancer (OR = 3.1, 95% CI = 2.4-4.2, p = 0.0002). Even after adjusting for age, sex and habit the AA-genotype is found to be significantly associated with oral cancer (OR = 2.4, 95% CI = 1.7-3.2, p = 0.0001). A protein-protein docking analysis demonstrated that in the GG-genotype the binding geometry between c-Jun Kinase and GSTP1 was disrupted. It was validated by immunohistochemistry in human samples, showing lower c-Jun-phosphorylation and down-regulation of pro-apoptotic genes in normal oral epithelial cells with the AA-genotype. In silico docking revealed that AA-genotype weakly detoxifies the RAN/tobacco metabolites. In addition, experiments revealed a higher level of 8-Oxo-2'deoxyguanosine induction in tumor samples with the AA-genotype. Thus, habit of using RAN/tobacco and GSTP1 AA-genotype together play a significant role in predisposition to oral cancer risk by showing higher DNA-lesions and lower c-Jun phosphorylation that may inhibit apoptosis.