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

Abstract

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 NorthEast 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. The oral squamous cell carcinoma (OSCC) is the most common cancer in India, with highest occurrence in the northeastern part of the country 1. The traditional habit of chewing raw rather than dry areca-nut with lime appears to be an important causative factor in addition of tobacco 2,3. In NorthEast India, particularly in Meghalaya, the betel-quid contains raw and unprocessed areca-nut (RAN), lime paste and small portion of betel-leaf but without tobacco. It has been noted that alkaloids, and polyphenols and tannic acid of RAN that are released in the saliva may contribute to carcinogenicity 4-6. It has been demonstrated that areca-nut alkaloids cause depression of antioxidants including glutathione and glutathione-S-transferases (GST) that are known to neutralize reactive oxygen species 7. Earlier studies indicate that RAN and lime together induce oral, esophagous and stomach cancers both in mouse and human and highlighted the occurrence of precocious anaphase (premature separation of sister-chromatids) and higher expression of p53 and Securin as a potential screening marker for identification of mitotic checkpoint defects during early days of RAN exposure 8,9. There are enough data to view lifestyle as well as genetic factors as important contributors for an individual's susceptibility to cancer 10. Glutathione redox and GST are supposed to play important roles in cellular

Glutathione S-Transferases S1, Z1 and A1 Serve as Prognostic Factors in Glioblastoma and Promote Drug Resistance through Antioxidant Pathways

“…The JNK pathway has been found to interact with multiple GST enzymes, including GSTP1 [ 37 , 38 , 39 ], and these interactions have been shown to promote apoptosis in glioma [ 40 , 41 , 42 ]. We thus hypothesized that the enhancing of drug resistance in GBM by HPGDS may be partially dependent on its inhibition of JNK pathway activation.…”

In silico analyses of the human sperm‐specific antigen 2 and its role in oral squamous cell carcinoma

“…The GSTP1 (control protein), a well‐known potential target protein in OSCC therapeutics [66], showed interaction with selected ligands (Table 4). The residues involved in interaction with carcinogens included Tyr‐8, Phe‐9, Gly‐13, Arg‐14, Trp‐39, Tyr‐50, Gln52, Leu‐53, Pro‐54, Gln‐65, Arg‐101, Tyr‐104, Ser‐106, Leu‐107, Gly‐115, Asp‐118, Tyr‐119, Ile‐162, and Ile‐204, while those interacting with therapeutants included Tyr‐8, Phe‐9, Arg‐12, Gly‐13, Arg‐14, Val‐36, Tyr‐50, Gln‐52, Leu‐53, Pro‐54, Tyr‐64, Gln‐65, Ser‐66, Arg‐101, Lys‐103, Tyr‐104, Ile‐105, Ser‐106, Leu‐107, Tyr‐109, Gly‐115, Tyr‐119, Leu‐161, Glu‐164, Val‐165, Pro‐203, Ile‐204, Asn‐205 Gly‐206, and Gly‐208.…”

“…The majority of OSCC carcinogens and therapeutants showed higher values of negative TBE for HSCP in comparison to GSTP1. Yadav and the group have reported interactions between areca nut metabolites and the GSTP1 protein, showing it as a favorable therapeutic target in oral cancers [66]. Similarly, HSCP is a strong candidate as a favorable therapeutic target in oral malignancy.…”

“…The TDS of the HSCP was overlapped with NCIs using the PyMOL molecular graphics system version 1.8 [65]. Additionally, the TDS of H. sapiens GSTP1 protein (P09211) was designed and validated [66].…”

“…The GSTP1 (control protein), a well-known potential target protein in OSCC therapeutics [66], showed interaction with selected ligands (Table 4). The residues involved in interaction with carcino- The majority of OSCC carcinogens and therapeutants showed higher values of negative TBE for HSCP in comparison to GSTP1.…”