Gene Summary

Gene:GSTP1; glutathione S-transferase pi 1
Aliases: PI, DFN7, GST3, GSTP, FAEES3, HEL-S-22
Summary:Glutathione S-transferases (GSTs) are a family of enzymes that play an important role in detoxification by catalyzing the conjugation of many hydrophobic and electrophilic compounds with reduced glutathione. Based on their biochemical, immunologic, and structural properties, the soluble GSTs are categorized into 4 main classes: alpha, mu, pi, and theta. This GST family member is a polymorphic gene encoding active, functionally different GSTP1 variant proteins that are thought to function in xenobiotic metabolism and play a role in susceptibility to cancer, and other diseases. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:glutathione S-transferase P
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: GSTP1 (cancer-related)

Zhou X, Jiao D, Dou M, et al.
Association of glutathione-S-transferase p1 gene promoter methylation and the incidence of prostate cancer: a systematic review and meta-analysis.
J Cancer Res Clin Oncol. 2019; 145(8):1939-1948 [PubMed] Related Publications
OBJECTIVE: Some studies have shown that the methylation status of the GSTP1 gene promoter is related to the incidence of prostate cancer, but this finding is still controversial. The aim of this study was to evaluate the association between glutathione-S-transferase p1 (GSTP1) promoter methylation and the incidence of prostate cancer.
METHODS: The Medline, Embase, Web of Science, and Cochrane CENTRAL databases were searched from their inception to February 22, 2019. According to the inclusion criteria, studies of the association between the methylation status of the GSTP1 gene promoter and prostate cancer were included. The difference in the incidence of GSTP1 promoter methylation in tissues, blood, or urine between patients with prostate cancer and those without prostate cancer were compared, and the results were expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed-effects model or a random-effects model to generate forest plots.
RESULTS: Ultimately, 15 studies (1540 samples) were included. The estimated effect from our meta-analysis showed that the incidence of GSTP1 promoter methylation was higher in patients with prostate cancer than in those without prostate cancer (OR 18.58, 95% CI 9.60-35.95, P = 0.000). GSTP1 promoter methylation was highly correlated with the incidence of prostate cancer.
CONCLUSIONS: Methylation of the GSTP1 promoter may increase the risk of prostate cancer. This study may provide a strategic direction for prostate cancer research. Pending validation of these findings, the methylation of the GSTP1 promoter may be a potential biomarker to diagnose prostate cancer.

Tjiong R, Stavrinou P, Röhn G, et al.
Heterogeneity of Human Gliomas: Glutathione-S-Transferase Expression Profile During Disease Progression and Under Systemic Therapy.
Anticancer Res. 2019; 39(4):1795-1805 [PubMed] Related Publications
BACKGROUND/AIM: The glutathione S-transferase pi gene (GSTP1) is a polymorphic gene encoding functionally different Gstp1 isoenzyme proteins. These seem to contribute to xenobiotic metabolism and might also play a role in susceptibility to cancer. The aim of this study was to elucidate the potential role of GSTP1 as a biomarker for disease progression and predictor of chemotherapeutic effect in glioma.
MATERIALS AND METHODS: Using quantitative real time PCR and western blotting analysis, a total of 61 astrocytic tumor samples from WHO grade II-IV were investigated.
RESULTS: There were no differences in GSTP1 mRNA expression between diffuse astrocytomas, anaplastic astrocytomas, or GBM. No difference was seen between secondary GBM before and after radio-/chemotherapy.
CONCLUSION: The expression of GSTP was highly heterogeneous within the surgical specimens. No significant differences in gene and protein expression were detected between the different types of gliomas, suggesting that glioma chemoresistance is probably multifactorial and GSTP1-independent.

Moghimi M, Sobhan MR, Jarahzadeh MH, et al.
Association of GSTM1, GSTT1, GSTM3, and GSTP1 Genes Polymorphisms with Susceptibility to Osteosarcoma: a Case- Control Study and Meta-Analysis
Asian Pac J Cancer Prev. 2019; 20(3):675-682 [PubMed] Related Publications
Background: Some studies have investigated the association of GSTM1, GSTT1, GSTM3, and GSTP1 polymorphisms with susceptibility to osteosarcoma; however, these studies results are inconsistent and inconclusive. In order to drive a more precise estimation, the present case-control study and meta-analysis was performed to investigate association of GSTM1, GSTT1, GSTM3, and GSTP1 polymorphisms with osteosarcoma. Methods: Eligible articles were identified by a search of several electronic databases for the period up to May 5, 2018. Odds ratios were pooled using either fixed-effects or random effects models. Results: Finally, a total of 24 case-control studies with 2,405 osteosarcoma cases and 3,293 controls were included in the present meta-analysis. Overall, significantly increased osteosarcoma risk was found when all studies were pooled into the meta-analysis of GSTT1 (Null vs. Present: OR= 1.247 95% CI 1.020-1.524, P= 0.031) and GSTP1 polymorphism (B vs. A: OR= 8.899 95% CI 2.722-29.094, P≤0.001). In the stratified, significantly increased osteosarcoma risk was observed for GSTT1 polymorphism among Asians (Null vs. Present: OR= 1.300 95% CI 1.034-1.635, P= 0.025), but not among Caucasians. Conclusions: This meta-analysis demonstrated that GSTP1 and GSTT1 null genotype are associated with the risk of osteosarcoma. Future large welldesigned epidemiological studies are warranted to validate our results.

Corno C, Perego P
KiSS1 in regulation of metastasis and response to antitumor drugs.
Drug Resist Updat. 2019; 42:12-21 [PubMed] Related Publications
Metastatic dissemination of tumor cells represents a major obstacle towards cancer cure. Tumor cells with metastatic capacity are often resistant to chemotherapy. Experimental efforts revealed that the metastatic cascade is a complex process that involves multiple positive and negative regulators. In this respect, several metastasis suppressor genes have been described. Here, we review the role of the metastasis suppressor KiSS1 in regulation of metastasis and in response to antitumor agents. Physiologically, KiSS1 plays a key role in the activation of the hypothalamic-pituitary-gonadal axis regulating puberty and reproductive functions. KiSS1-derived peptides i.e., kisspeptins, signal through the G-protein coupled receptor GPR54. In cancer, KiSS1 signaling suppresses metastases and maintains dormancy of disseminated malignant cells, by interfering with cell migratory and invasive abilities. Besides, KiSS1 modulates glucose and lipid metabolism, by reprogramming energy production towards oxidative phosphorylation and β-oxidation. Loss or reduced expression of KiSS1, in part through promoter hypermethylation, is related to the development of metastases in various cancer types, with some conflicting reports. The poorly understood role of KiSS1 in response to chemotherapeutic agents appears to be linked to stimulation of the intrinsic apoptotic pathway and inhibition of cell defense factors (e.g., glutathione S-transferase-π) as well as autophagy modulation. Deciphering the molecular basis underlying regulation of the metastatic potential is crucial for the establishment of novel treatment strategies.

Wang S, Zhang J, Jun F, Bai Z
Glutathione S-transferase pi 1 variant and squamous cell carcinoma susceptibility: a meta-analysis of 52 case-control studies.
BMC Med Genet. 2019; 20(1):22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There are several meta-analyses on the genetic relationship between the rs1695 polymorphism within the GSTP1 (glutathione S-transferase pi 1) gene and the risk of different SCC (squamous cell carcinoma) diseases, such as ESCC (oesophageal SCC), HNSCC (head and neck SCC), LSCC (lung SCC), and SSCC (skin SCC). Nevertheless, no unified conclusions have been drawn.
METHODS: Herein, an updated meta-analysis was performed to evaluate the probable impact of GSTP1 rs1695 on the susceptibility to different SCC diseases under six genetic models (allele, carrier, homozygote, heterozygote, dominant, and recessive). Three online databases, namely, PubMed, WOS (Web of Science), and Embase (Excerpta Medica Database), were searched.
RESULTS: Initially, we obtained a total of 497 articles. Based on our selection criteria, we eventually included 52 case-control studies (9763 cases/15,028 controls) from 47 eligible articles. As shown in the pooling analysis, there was no difference in the risk of overall SCC disease between cases and controls [allele, P
CONCLUSION: The rs1695 polymorphism within the GSTP1 gene is not associated with the risk of overall SCC or a specific SCC type, including ESCC, HNSCC, LSCC, and SSCC.

Zhang Y, Zhang H, Lin P, Zhang G
Glutathione S-transferase gene polymorphisms and risk of nasal or colorectal polyposis.
Biosci Rep. 2019; 39(1) [PubMed] Free Access to Full Article Related Publications
We observed inconsistent conclusions regarding the genetic role of glutathione S-transferase gene polymorphisms, including glutathione S-transferase M1 (

Song B, Wang L, Zhang Y, et al.
Combined Detection of HER2, Ki67, and GSTP1 Genes on the Diagnosis and Prognosis of Breast Cancer.
Cancer Biother Radiopharm. 2019; 34(2):85-90 [PubMed] Related Publications
OBJECTIVE: Breast cancer (BC) is a common malignant tumor in females. The combined assay of multiple molecular markers benefits the diagnosis and prognostic prediction. Human epidermal growth factor receptor 2 (HER2) facilitates the proliferation and differentiation of cancer cells through ligand binding. Ki67 is a tumor proliferation-related gene, whereas GSTP1 is a DNA repair-related gene. This study thus investigated the significance of HER2 and Ki67/GSTP1 gene combined assay in the diagnosis and prognosis of BC.
MATERIALS AND METHODS: A total of 86 breast tumor tissues and adjacent tissues were collected. Gene expression and protein levels of HER2 and Ki67 were quantified by real-time polymerase chain reaction (PCR) and Western blot, respectively. Methylation frequency of GSTP1 was analyzed by methylation-specific PCR. The correlation between HER2 and Ki67/GSTP1 and clinical/pathological features of BC was analyzed.
RESULTS: Gene and protein expression levels of HER2 and Ki67 in tumor tissues were increased (p < 0.05 compared with adjacent tissues). Methylation frequency of GSTP1 gene was 37.2%, which was significantly higher in breast tumor tissues than in adjacent tissues (12.79%, p < 0.05). HER2 expression was positively correlated with TNM stage, tumor size, and lymph node metastasis, and negatively correlated with tissue grade and estrogen receptor (ER)/progesterone receptor (PR) expression (p < 0.05). GSTP1 methylation was positively correlated with TNM stage and tumor size, and negatively correlated with ER/PR expression (p < 0.05).
CONCLUSIONS: HER2, Ki67, and GSTP1 methylation were correlated with clinical and pathological features of BC. The combined assay benefits the early diagnosis and prognostic prediction of cancer.

Liu WZ, Sun Y, Feng X, et al.
An updated meta-analysis for association of glutathione S-transferase P1 gene polymorphism with the susceptibility of lung cancer.
J Cancer Res Ther. 2018; 14(Supplement):S1084-S1090 [PubMed] Related Publications
Aim of Study: The conclusions on the association between glutathione S-transferase P1 (GSTP1) gene polymorphism and lung cancer risk are still debated. This meta-analysis was performed to update the association between GSTP1 and the risk of lung cancer.
Materials and Methods: The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method.
Results: Fifty reports were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and lung cancer susceptibility. The association between GSTPI G allele/GG genotype and lung cancer risk was found in this meta-analysis (G allele: odds ratio [OR] = 1.08, 95% confidence interval [CI]: 1.02-1.14, P = 0.006; GG genotype: OR = 1.09, 95% CI: 1.00-1.18, P = 0.04). However, the AA genotype was not associated with the susceptibility of lung cancer.
Conclusion: GSTP1 G allele/GG genotype is associated with the lung cancer susceptibility.

Ogino S, Konishi H, Ichikawa D, et al.
Glutathione S-transferase Pi 1 is a valuable predictor for cancer drug resistance in esophageal squamous cell carcinoma.
Cancer Sci. 2019; 110(2):795-804 [PubMed] Free Access to Full Article Related Publications
Esophageal squamous cell carcinoma (ESCC) is a lethal malignancy. However, there are few useful markers for diagnosis and treatment. Glutathione S-transferase Pi 1 (GSTP1) has been reported as a predictor of malignancy or anticancer drug resistance in some cancers. We investigated the association of GSTP1 expression with the malignancy or drug resistance in ESCC cell lines and clinical tissue samples. Proliferation and apoptosis assays regarding GSTP1 expression were examined in ESCC cell lines. Proliferation of GSTP1 knockdown cells was significantly decreased (P < .01), and the frequency of early apoptosis was increased (P < .05). Invasion capacity of GSTP1 knockdown cells was slightly decreased in transwell assay. These results suggest that GSTP1 plays an important role in malignant potential. To examine the effects of GSTP1 on drug resistance, chemosensitivity assay and apoptosis assay under cisplatin exposure were carried out. Viability of GSTP1 knockdown cells treated with cisplatin was lower than that of control cells (P < .01). Moreover, the frequency of early and late apoptosis in GSTP1 knockdown cells was markedly increased over that of control cells by cisplatin exposure (P < .01). In immunohistochemistry assay of resected tissue samples, GSTP1 expression was significantly associated with clinical downstaging (P = .04) in 72 ESCC patients with neoadjuvant chemotherapy. Furthermore, there was a significant association between GSTP1 expression in resected tissue and biopsy samples in 34 ESCC patients without neoadjuvant chemotherapy (P = .02). In summary, GSTP1 was related to malignant potential and may be a predictive marker of drug resistance in ESCC patients.

Zhao F, Olkhov-Mitsel E, Kamdar S, et al.
A urine-based DNA methylation assay, ProCUrE, to identify clinically significant prostate cancer.
Clin Epigenetics. 2018; 10(1):147 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Prevention of unnecessary biopsies and overtreatment of indolent disease remains a challenge in the management of prostate cancer. Novel non-invasive tests that can identify clinically significant (intermediate-risk and high-risk) diseases are needed to improve risk stratification and monitoring of prostate cancer patients. Here, we investigated a panel of six DNA methylation biomarkers in urine samples collected post-digital rectal exam from patients undergoing prostate biopsy, for their utility to guide decision making for diagnostic biopsy and early detection of aggressive prostate cancer.
RESULTS: We recruited 408 patients in risk categories ranging from benign to low-, intermediate-, and high-risk prostate cancer from three international cohorts. Patients were separated into 2/3 training and 1/3 validation cohorts. Methylation biomarkers were analyzed in post-digital rectal exam urinary sediment DNA by quantitative MethyLight assay and investigated for their association with any or aggressive prostate cancers. We developed a Prostate Cancer Urinary Epigenetic (ProCUrE) assay based on an optimal two-gene (HOXD3 and GSTP1) LASSO model, derived from methylation values in the training cohort, and assessed ProCUrE's diagnostic and prognostic ability for prostate cancer in both the training and validation cohorts. ProCUrE demonstrated improved prostate cancer diagnosis and identification of patients with clinically significant disease in both the training and validation cohorts. Using three different risk stratification criteria (Gleason score, D'Amico criteria, and CAPRA score), we found that the positive predictive value for ProCUrE was higher (59.4-78%) than prostate specific antigen (PSA) (38.2-72.1%) for all risk category comparisons. ProCUrE also demonstrated additive value to PSA in identifying GS ≥ 7 PCa compared to PSA alone (DeLong's test p = 0.039), as well as additive value to the PCPT risk calculator for identifying any PCa and GS ≥ 7 PCa (DeLong's test p = 0.011 and 0.022, respectively).
CONCLUSIONS: ProCUrE is a promising non-invasive urinary methylation assay for the early detection and prognostication of prostate cancer. ProCUrE has the potential to supplement PSA testing to identify patients with clinically significant prostate cancer.

Qiu J, Du Z, Liu J, et al.
Association between polymorphisms in estrogen metabolism genes and breast cancer development in Chinese women: A prospective case-control study.
Medicine (Baltimore). 2018; 97(47):e13337 [PubMed] Free Access to Full Article Related Publications
We comprehensively identified polymorphisms in estrogen-metabolizing genes that may be associated with breast cancer initiation in Chinese women, via an ongoing prospective case-control study.An ongoing prospective case-control study of 427 female case patients diagnosed with breast cancer from August 2013 to March 2015 and 536 women (case controls) with no prior history of cancer or benign breast tumors was performed. Buccal cell specimens were obtained using the cotton swabbing method. DNA was extracted from the buccal cells using the phenol/chloroform method. Genotype was carried out for 5 single nucleotide polymorphisms (rs4646903, rs1056836, rs1695, rs4970737, and rs4680) using direct sequencing.The polymorphic genotypes of glutathione S-transferase (GSTP1) (P = .044) and catechol-O-methyltransferase (COMT) (P = .008) showed significantly different distributions, while that of cytochrome P450 (CYP1B1) (P = .051) showed a slight difference in distribution between healthy women and patients with breast cancer. Individuals with homozygous variant genotypes for GSTP1 or COMT exhibited a higher risk of developing breast cancer than those with wild-type genotypes; however, for CYP1B1, the homozygous variant genotype was associated with a lower risk, and the heterozygous genotype for these 3 genes was not associated with breast cancer development.An individual's risk of breast cancer is only influenced by the specific combination of risk-associated alleles of COMT and GSTP1, despite the protective effects of the homozygous CYP1B1 genotype revealed by univariate analysis.

Zou M, Hu X, Xu B, et al.
Glutathione S‑transferase isozyme alpha 1 is predominantly involved in the cisplatin resistance of common types of solid cancer.
Oncol Rep. 2019; 41(2):989-998 [PubMed] Related Publications
The roles of glutathione S‑transferase pi 1 (GSTP1), glutathione S‑transferase mu 2 (GSTM2) and glutathione S‑transferase alpha 1 (GSTA1) in cisplatin (DDP)‑resistance of solid cancer cells (A549/DDP, SKOV3/DDP and SGC7901/DDP) were compared following expression downregulation with small interfering RNAs (siRNAs). DDP cytotoxicity was reflected by its half maximal inhibition concentration (IC50) calculated from data using a Cell Counting Kit‑8 assay; cell apoptosis was examined using flow cytometry and Hoechst 33342 staining. Higher activities of GST were detected in the cytosol of DDP‑resistant cells, compared with those in the parental DDP‑susceptible cells. The silencing efficacy of each positive siRNA was supported by western blot analysis. GSTP1 silencing resulted in a 4‑fold sensitization of SGC7901/DDP cells to DDP cytotoxicity, but negligible sensitization of SKOV3/DDP and A549/DDP cells. GSTM2 silencing sensitized SKOV3/DDP and A549/DDP cells to DDP cytotoxicity by ~2‑fold, but did not sensitize SGC7901/DDP cells. Notably, GSTA1 silencing enhanced DDP cytotoxicity in SGC7901/DDP cells by 6‑fold, in A549/DDP cells by 5‑fold and in SKOV3/DDP cells by 2‑fold. The combined actions of positive siRNAs and DDP increased the percentages of apoptotic cells in the DDP‑resistant solid cancer cells compared with the combined actions of DDP and the negative siRNAs. The present findings indicated that GSTA1 is a predominant GST isozyme associated with DDP resistance of SGC7901/DDP, A549/DDP and SKOV3/DDP cells; GSTA1‑specific inhibitors may be general sensitizers of SGC7901/DDP, A549/DDP and SKOV3/DDP cells to DDP cytotoxicity through the promotion of cell apoptosis.

Zhou T, Li HY, Xie WJ, et al.
Association of Glutathione S-transferase gene polymorphism with bladder Cancer susceptibility.
BMC Cancer. 2018; 18(1):1088 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We conducted a meta-analysis to evaluate the relationship between the glutathione S-transferase μ1 (GSTM1)- and glutathione S-transferase θ1 (GSTT1)- null genotypes and susceptibility to bladder cancer.
METHODS: We identified association reports from the databases of PubMed, Embase, the Cochrane Library and the China Biological Medicine Database (CBM disc) on July 1, 2017 and synthesized eligible investigations. Results were expressed using odds ratios (ORs) for dichotomous data, and we also calculated 95% confidence intervals (CIs).
RESULTS: In this meta-analysis, we found that the GSTM1-null genotype was associated with bladder cancer risk in the overall population, and individually in whites, Africans and Asians (overall population: OR = 1.40, 95% CI: 1.31-1.48, P<0.00001; whites: OR = 1.39, 95% CI: 1.26-1.54, P<0.00001; Africans: OR = 1.54, 95% CI: 1.16-2.05, P = 0.003; Asians: OR = 1.45, 95% CI: 1.33-1.59, P<0.00001). The GSTT1-null genotype was associated with bladder cancer risk in the overall population, but not in whites, in Africans or Asians (overall population: OR = 1.11, 95% CI: 1.01-1.22, P = 0.03; whites: OR = 1.16, 95% CI: 0.99-1.36, P = 0.07; Africans: OR = 1.07, 95% CI: 0.65-1.76, P = 0.79; Asians: OR = 1.05, 95% CI: 0.91-1.22, P = 0.51). Interestingly, a dual-null GSTM1-GSTT1 genotype was associated with bladder cancer risk in the overall population and in Asians (overall population: OR = 1.48, 95% CI: 1.15-1.92, P = 0.002; Asians: OR = 1.62, 95% CI: 1.15-2.28, P = 0.006). In conclusion, the GSTM1-null, GSTT1-null and dual-null GSTM1-GSTT1 genotypes might be associated with the onset of bladder cancer, but additional genetic-epidemiological studies should be conducted to explore this association further.

Moreira-Barbosa C, Barros-Silva D, Costa-Pinheiro P, et al.
Comparing diagnostic and prognostic performance of two-gene promoter methylation panels in tissue biopsies and urines of prostate cancer patients.
Clin Epigenetics. 2018; 10(1):132 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Prostate cancer (PCa) is one of the most common cancers among men worldwide. Current screening methods for PCa display limited sensitivity and specificity, not stratifying for disease aggressiveness. Hence, development and validation of new molecular markers is needed. Aberrant gene promoter methylation is common in PCa and has shown promise as clinical biomarker. Herein, we assessed and compared the diagnostic and prognostic performance of two-gene panel promoter methylation in the same sample sets.
METHODS: Promoter methylation of panel #1 (singleplex-miR-34b/c and miR-193b) and panel #2 (multiplex-APC, GSTP1, and RARβ2) was evaluated using MethyLight methodology in two different cohorts [prostate biopsy (#1) and urine sediment (#2)]. Biomarkers' diagnostic (validity estimates) and prognostic (disease-specific survival, disease-free survival, and progression-free survival) performance was assessed.
RESULTS: Promoter methylation levels of both panels showed the highest levels in PCa samples in both cohorts. In tissue samples, methylation panel #1 and panel #2 detected PCa with AUC of 0.9775 and 1.0, respectively, whereas in urine samples, panel #2 demonstrated superior performance although a combination of miR-34b/c, miR-193b, APC, and RARβ2 disclosed the best results (AUC = 0.9817). Furthermore, higher mir-34b/c and panel #2 methylation independently predicted for shorter DSS. Furthermore, time-dependent ROC curves showed that both miR-34b/c and GSTP1 methylation levels identify with impressive performance patients that relapse up to 15 years after diagnosis (AUC = 0.751 and AUC = 0.765, respectively).
CONCLUSIONS: We concluded that quantitative gene panel promoter methylation might be a clinically useful tool for PCa non-invasive detection and risk stratification for disease aggressiveness in both tissue biopsies and urines.

Ghanbarian M, Afgar A, Yadegarazari R, et al.
Through oxaliplatin resistance induction in colorectal cancer cells, increasing ABCB1 level accompanies decreasing level of miR-302c-5p, miR-3664-5p and miR-129-5p.
Biomed Pharmacother. 2018; 108:1070-1080 [PubMed] Related Publications
Oxaliplatin as a component of (Neo-) adjuvant chemotherapeutic regimens is administered to colorectal cancer patients. Unfortunately, the acquisition of resistance to this drug in nearly 90% of metastatic patients rendered it as an ineffective drug. Therefore, resistance mechanisms to this drug should be elucidated. There are different genes like GSTP1 and ABCB1 which are responsible for oxaliplatin resistance. We hypothesized that miR-129-5p, miR-302c-5p, miR-3664-5p, mir-3714 and miR-513a-3p are targeting ABCB1 gene, while GSTP1 was predicted to be the potential target of miR-3664-5p, mir-3714 and miR-513a-3p. In order to study this hypothesis, resistant colorectal cell lines were generated through intermittent exposure of HCT116, SW480 and HT29 to the increasing doses of oxaliplatin. MTT assays validated this resistance induction. Expression of ABCB1 and GSTP1 in addition to their targeting miRNAs in different cell lines were studied by quantitative real time PCR in the cell lines. Even though in comparison with HCT116 and SW480 cell lines, GSTP1 expression was reduced in resistant cells, ABCB1 expression was upregulated in these cell lines. On the other hand, HT-29 resistant cells showed elevated GSTP1 and unchanged ABCB1 levels. While miR-302c-5p level was downregulated in resistant cell lines, miR-129-5p and miR-3664-5p level showed different pattern of reduction in the resistant SW480 and HCT116 cell lines. GSTP1 level was correlated directly with miR-513a-3p and miR-3664-5p in all SW480 and HCT116 derived cell lines, however in HT-29-OXR1, GSTP1 level was correlated inversely with miR-3664-5p. In conclusion, upregulation of ABCB1 can be considered as the crucial component of poor response to oxaliplatin which is likely controlled by miR-302c-5p.

Rodrigues-Fleming GH, Fernandes GMM, Russo A, et al.
Molecular evaluation of glutathione S transferase family genes in patients with sporadic colorectal cancer.
World J Gastroenterol. 2018; 24(39):4462-4471 [PubMed] Free Access to Full Article Related Publications
AIM: To evaluate the association between polymorphisms in glutathione S transferases (GSTs) and the risk of sporadic colorectal cancer (SCRC), tumor progression and the survival of patients.
METHODS: A case-control study of 970 individuals from the Brazilian population was conducted (232 individuals from the case group with colorectal cancer and 738 individuals from the control group without a history of cancer). PCR multiplex and PCR-RFLP techniques were used to genotype the GST polymorphisms. The tumors were categorized according to the TNM classification: tumor extension (T), affected lymph nodes (N), and presence of metastasis (M). Logistic regression, multiple logistic regression and survival analysis were used to analyze the data. The results are presented in terms of odds ratio (OR) and 95% confidence interval (CI). The level of significance was set at 5% (
RESULTS: Age equal to or over 62 years (OR = 8.79; 95%CI: 5.90-13.09,
CONCLUSION: Females aged 62 years or older are more susceptible to SCRC. Polymorphisms of

Wang H, Gao X, Zhang X, et al.
Glutathione S-Transferase Gene Polymorphisms are Associated with an Improved Treatment Response to Cisplatin-Based Chemotherapy in Patients with Non-Small Cell Lung Cancer (NSCLC): A Meta-Analysis.
Med Sci Monit. 2018; 24:7482-7492 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Previous studies have shown an association with glutathione S-transferase (GST) gene polymorphisms in patients with non-small cell lung cancer (NSCLC) and treatment response. This study aimed to undertake a literature review and meta-analysis of GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1 IIe105Val, and the treatment response to cisplatin-based chemotherapy in patients with NSCLC. MATERIAL AND METHODS A literature search was undertaken of the main medical publication databases for publications, up to March 2017, on the association between GSTT1, GSTM1, and GSTP1 IIe105Val polymorphisms and the clinical outcome in patients with NSCLC treated with cisplatin-based chemotherapy. A random fixed-effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate the associations, considering multiple genetic models. A subgroup analysis according to ethnicity was performed. RESULTS Twenty-three published studies were identified that showed that both the null GSTM1 and the GG genotype of GSTP1 IIe105Val were associated with improved treatment response to cisplatin-based chemotherapy (GSTT1 present/null: OR=1.328; 95% CI, 1.074-1.643) (GSTP1 GG + AG vs. AA: OR=0.596; 95% CI, 0.468-0.759). In subgroup analysis, the GSTP1 polymorphism was significantly associated with treatment response in East-Asian patients, but not in Caucasian patients. CONCLUSIONS Meta-analysis showed that the GG genotype of GSTP1 IIe105Val and the null GSTM1 genotype were associated with an improved treatment response to cisplatin-based chemotherapy in patients with NSCLC, especially in East-Asian patients.

Yang F, Gao B, Chen W, et al.
Expression of resistance gene and prognosis of chemotherapy in primary epithelial ovarian cancer.
Medicine (Baltimore). 2018; 97(41):e12364 [PubMed] Free Access to Full Article Related Publications
The sensitivity of tumor cells to chemotherapy drugs may become attenuated accounts for various reasons. Reduced drug sensitivity may cause the failure of chemotherapy and affect the prognosis of patients with cancer. This study investigates the relationship between the expression levels of lung resistance protein (LRP) and placental glutathione S-transferase-P1 (GSTP1), the resistance of primary epithelial ovarian cancer (PEOC) to chemotherapy, and the prognosis of patients with platinum drug-resistant PEOC.Quantitative PCR (QT-PCR) was used to detect the mRNA level of the resistance genes LRP, GSTP1 in all tissue and cell lines.The expression levels of resistance gene (LRP, GSTP1) in PEOC were the highest, followed by borderline adenoma tissues, and the lowest levels found in benign tumor tissues, the difference of genes expression between different tissues was statistically significant; the difference between the expression rates and relative expression level of drug resistance genes was statistically significant in platinum sensitive group compare with the platinum resistant group. The difference between resistant gene negative-expression and positive-expression of chemotherapy efficiency, disease free survival time, and recurrence time were statistically significant. The resistant genes expression in the PEOC patients of the negative-group survival curves was higher than that in the positive group. With ascites non-cellular component (ANCC) stimulated SKOV3 cells, the cell proliferation inhibition rate (CPIR) increased, and with ANCC stimulated SKOV3/DDP, the expression of LRP and GSTP1 also increased.ANCC may promote the expression of drug resistance genes, and the expression of genes may predict the poorly prognosis of epithelial ovarian cancer.

Chen M, Du D, Zheng W, et al.
Small hepatitis delta antigen selectively binds to target mRNA in hepatic cells: a potential mechanism by which hepatitis D virus downregulates glutathione S-transferase P1 and induces liver injury and hepatocarcinogenesis.
Biochem Cell Biol. 2019; 97(2):130-139 [PubMed] Related Publications
Liver coinfection by hepatitis B virus (HBV) and hepatitis D virus (HDV) can result in a severe form of hepatocellular carcinoma with poor prognosis. Coinfection with HDV and HBV causes more deleterious effects than infection with HBV alone. Clinical research has shown that glutathione S-transferase P1 (GSTP1), a tumor suppressor gene, is typically downregulated in liver samples from hepatitis-infected patients. In the present study, our data indicated that small HDV antigen (s-HDAg) could specifically bind to GSTP1 mRNA and significantly downregulate GSTP1 protein expression. For the human fetal hepatocyte cell line L-02, cells transfected with s-HDAg, along with decreased GSTP1 expression, there was a significant accumulation of reactive oxygen species (ROS) and increased apoptotic ratios. Restoring GSTP1 expression through silencing s-HDAg via RNAi or overexpressing exogenous GSTP1 could largely recover the abnormal cell status. Our results revealed a novel potential mechanism of HDV-induced liver injury and hepatocarcinogenesis: s-HDAg can inhibit GSTP1 expression by directly binding to GSTP1 mRNA, which leads to accumulation of cellular ROS, resulting in high cellular apoptotic ratios and increased selective pressure for malignant transformation. To our knowledge, this is the first study to examine s-HDAg-specific pathogenic mechanisms through potential protein-RNA interactions.

Salvi S, Casadio V, Martignano F, et al.
Carcinosarcoma of the prostate: case report with molecular and histological characterization.
Int J Biol Markers. 2018; 33(4):540-544 [PubMed] Related Publications
BACKGROUND:: We report a case of prostatic carcinosarcoma, a rare variant of prostatic cancer, which is composed of a mixture of epithelial and mesenchymal components with a generally poor outcome.
AIMS AND METHODS:: We aim to identify molecular alterations, in particular copy number variations of AR and c -MYC genes, methylation and expression of glutathione S-transferase P1 (GSTP1), programmed death-ligand 1 (PD-L1), AR, and phosphorylated AR expression.
RESULTS:: We found a distinct molecular pattern between adenocarcinoma and carcinosarcoma, which was characterized by high AR copy number variation gain; positive expression of PD-L1, AR, and phosphorylated AR; low espression of GSTP1 in epithelial component. The sarcomatoid component had a lower gain of the AR gene, and no expression of PD-L1, AR, phosphorylated AR, or GSTP1. Both components had a gain of c-MYC copy number variation.
CONCLUSIONS:: Our findings suggest that carcinosarcoma has specific molecular characteristics that could be indicative for early diagnosis and treatment selection.

Bulus H, Oguztuzun S, Güler Simsek G, et al.
Expression of CYP and GST in human normal and colon tumor tissues.
Biotech Histochem. 2019; 94(1):1-9 [PubMed] Related Publications
We investigated the immunohistochemical staining characteristics of cytochrome P450 1A1 (CYP1A1), CYPB1, CYP2E1, and glutathione S-transferase P1 (GSTP1), GSTT1, GSTO1, GSTK1 in colon tumor and surrounding normal colon tissues. Tissues were obtained from 47 patients with colon adenocarcinoma and the staining intensity of tumor and control tissues was compared. CYP1A1, CYP1B1, CYP2E1, GSTP1, GSTT1, GSTO1 and GSTK1 expressions in colon cancer cells were significantly greater than those in normal colon epithelial cells. No significant relation was found between the isoenzyme expressions and age, gender, smoking status, tumor grade and tumor stage. The higher expressions of CYP1A1, CYP1B1, CYP2E1, GSTP1, GSTO1, GSTT1 and GSTK1 in tumor than in normal colon tissues may be important for colon cancer progression and development.

Vu TL, Nguyen TT, Doan VTH, Vo LTT
Methylation Profiles of BRCA1, RASSF1A and GSTP1 in Vietnamese Women with Breast Cancer
Asian Pac J Cancer Prev. 2018; 19(7):1887-1893 [PubMed] Free Access to Full Article Related Publications
Objective: This study investigated the DNA promoter methylation profiles of BRCA1, RASSF1A and GSTP1 genes, both individually and in an integrative manner in order to clarify their correlation with clinicopathological parameters of breast cancer from Vietnamese patients, and establish new potential integrative methylation biomarkers for breast cancer detection. Material and methods: The methylation frequencies of BRCA1, RASSF1A and GSTP1 were analyzed by methylation specific polymerase chain reaction (MSP) in 70 specimens of breast carcinomas and 79 pairs of tumor and matched adjacent normal tissues from breast cancer patients. Results: All the three analyzed genes showed a concordance concerning their promoter methylation in tumor and adjacent normal tissue. The methylation of BRCA1, RASSF1A and GSTP1 was found in 58.23 %, 74.68 % and 59.49 % of tumor tissues and 51.90 %, 63.29 % and 35.44 % of corresponding adjacent tissues, respectively. When each gene was assessed individually, only the methylation of GSTP1 was significantly associated with tumor tissues (p=0.003). However, the methylation frequency of at least one of the three genes and the methylation frequency of all the three genes both showed significant association with tumor (p=0.008 and p=0.04, respectively). The methylation of BRCA1 was found to be significantly associated with tumor grade (p=0.01). Conclusion: This study emphasized that the panel of the three genes BRCA1, RASSF1A and GSTP1 can be further developed as potential biomarkers in diagnosis and classification of breast cancer in Vietnamese women.

Hadami K, Dakka N, Bensaid M, et al.
Evaluation of glutathione S-transferase pi 1 expression and gene promoter methylation in Moroccan patients with urothelial bladder cancer.
Mol Genet Genomic Med. 2018; 6(5):819-827 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glutathione S-transferase pi 1 (GSTP1) is a cytosolic detoxifying enzyme that protects cells against deleterious effects of oxidative stress. Deregulated expression of GSTP1 protein and aberrant promoter methylation of GSTP1 gene were reported in various human tumors and were shown to be involved in the molecular pathway for cancer development.
AIMS AND METHODS: In this study, we aimed to determine the expression status of GSTP1 in relation to its gene promoter methylation in Moroccan population of 30 bladder cancer (BC) patients and in two noncancerous bladder tissues used as controls. GSTP1 expression was assessed by immunohistochemistry and GSTP1 gene promoter methylation status was studied by methylation-specific PCR (MS-PCR).
RESULTS: Glutathione S-transferase pi 1 was expressed in the two normal tissues. In BC cases, GSTP1 expression was strong in 23.33% (7/30), moderate in 60% (18/30), and weak in 13.33% (4/30) of cases, while GSTP1 was not expressed in one cancer case (3.33%). Variability of GSTP1 expression does not correlate with high-grade cancer or invasive-stage (p > 0.05). No GSTP1 gene promoter methylation was detected in all control and cancer cases.
CONCLUSION: Our data suggest that GSTP1 expression is not associated with BC development, limiting its use as a biomarker for BC management in Morocco. Moreover, difference in GSTP1 expression among BC cases is not due to GSTP1 promoter methylation.

Carta A, Pavanello S, Mastrangelo G, et al.
Impact of Occupational Exposures and Genetic Polymorphisms on Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer.
Int J Environ Res Public Health. 2018; 15(8) [PubMed] Free Access to Full Article Related Publications

Li Y, Cai Y, Chen H, Mao L
Clinical significance and association of GSTP1 hypermethylation with hepatocellular carcinoma: A meta-analysis.
J Cancer Res Ther. 2018; 14(Supplement):S486-S489 [PubMed] Related Publications
Objective: To quantitatively investigate the effect of GSTP1 hypermethylation on hepatocellular carcinoma (HCC) using a meta-analysis of available case-control studies.
Materials and Methods: Previous studies have primarily evaluated the incidence of GSTP1 hypermethylation in HCC and corresponding control groups, and compared the incidence of GSTP1 hypermethylation in tumor tissues, pericancer liver tissues, normal liver issues, and nontumor liver tissues with that in other diseases. Data regarding publication information, study characteristics, and incidence of GSTP1 hypermethylation in both groups were collected from these studies and summarized. Eleven studies, including 546 cases of HCC and 575 nontumor cases, were identified for meta-analysis.
Results: Statistically significant odds ratios (ORs) of GSTP1 hypermethylation were obtained from tumor tissues and nontumorous liver tissues of HCC patients (OR 2.63, 95% confidence interval [CI]: 1.77-3.89%, P < 0.0001), tumor tissues of HCC patients, healthy liver tissues of patients with other diseases (OR 7.29, 95% CI: 2.87-18.51%, P < 0.0001), tumor tissues of HCC patients, and liver tissues of patients with nontumorous liver diseases (OR 2.13, 95% CI: 1.10-4.13%, P < 0.05). The pooled analysis showed significantly increased ORs of GSTP1 hypermethylation (OR 2.21, 95% CI: 1.01-4.84%, P < 0.05) from HCC tissues and cirrhotic tissues.
Conclusions: The results of this meta-analysis suggest that GSTP1 hypermethylation induces the inactivation of GSTP1 gene, plays an important role in hepatocarcinogenesis, and is associated with an increased risk of HCC.

Chatterjee A, Gupta S
The multifaceted role of glutathione S-transferases in cancer.
Cancer Lett. 2018; 433:33-42 [PubMed] Related Publications
Glutathione S-transferases (GSTs) are phase II detoxifying enzymes involved in the maintenance of cell integrity, oxidative stress and protection against DNA damage by catalyzing the conjugation of glutathione to a wide variety of electrophilic substrates. Though enzymes of the glutathione synthesis and salvage pathways have been well characterized in the past, there is still a lack of comprehensive understanding of their independent and coordinate regulatory mechanisms in carcinogenesis. The present review discusses implication of GST in cancer development and progression, gene polymorphism, drug resistance, signaling and epigenetic regulation involving their role in cancer. It is anticipated that GST especially the GSTP1 class can be developed as a biomarker either used alone or in combination with other biomarkers for early cancer detection and/or diagnosis as well as for future targeted preventive and therapeutic interventions with dietary agents.

Palugulla S, Devaraju P, Kayal S, et al.
Genetic polymorphisms in cyclin H gene are associated with oxaliplatin-induced acute peripheral neuropathy in South Indian digestive tract cancer patients.
Cancer Chemother Pharmacol. 2018; 82(3):421-428 [PubMed] Related Publications
PURPOSE: Digestive tract cancer patients treated with oxaliplatin are often associated with the development of peripheral neuropathy. The aim of the present study is to identify the influence of single-nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin metabolism, cell cycle control, detoxification or excretion pathways with the development of oxaliplatin-induced acute peripheral neuropathy (acute OXAIPN) and its severity among digestive tract cancer patients treated with oxaliplatin-based chemotherapy.
PATIENTS AND METHODS: A total of 228 digestive tract cancer patients undergoing with the oxaliplatin-based chemotherapy between November 2014 and December 2016 were included in the current study. Genomic DNA was extracted from peripheral blood by standard phenol-chloroform method. Genotyping of five SNPs in four genes [GSTP
RESULTS: We found that the two genetic variants rs2230641 and rs3093816 in cyclin H (CCNH) gene were significantly associated with both the incidence and severity of acute OXAIPN. For CCNH-rs2230641 (AA vs AG+GG; dominant model) Incidence: OR 2.62, 95% CI 1.44-4.75, p = 0.001, severity; OR 4.64, 95% CI 1.58-13.62, p = 0.002. For CCNH-rs3093816 (AA vs AG+GG; dominant model); incidence: OR 3.43, 95% CI 1.57-7.50, p = 0.001; severity: OR 2.36, 95% CI 1.05-5.30, p = 0.033.
CONCLUSIONS: The results of the present study found significant association between CCNH polymorphisms and acute OXAIPN development. However, further studies are warranted from independent groups to validate our study results.

Abbas M, Kushwaha VS, Srivastava K, et al.
Impact of GSTM1, GSTT1 and GSTP1 genes polymorphisms on clinical toxicities and response to concomitant chemoradiotherapy in cervical cancer.
Br J Biomed Sci. 2018; 75(4):169-174 [PubMed] Related Publications
BACKGROUND: Certain forms of chemoradiotherapy generate toxic reactive oxygen species, which may be ameliorated by antioxidant enzymes such as glutathione S-transferase (GST). Genetic polymorphisms of GST may predict treatment outcomes and can be used as genetic marker to screen patients before treatment. We hypothesised an effect of GST polymorphisms on the response and toxicities produced by chemoradiation therapy.
MATERIALS AND METHODS: GST polymorphisms were determined by multiplex polymerase chain reaction and PCR-restriction fragment length polymorphism (PCR-RFLP) in 227 women with cervical cancer receiving cisplatin based chemoradiotherapy. Treatment response and toxicities were evaluated by standard internationally recognised criteria (RECIST and RTOG).
RESULTS: Severe (grade 3-4) gastrointestinal and haematological toxicities were present in 22 (9.4%) and 16 (7.0%) patients, respectively. GSTM1 null, GSTT1 null and GSTP1 AG genotypes brought marginally better non-significant associations. In single locus analysis GSTP1 AG and GG was linked to greatest risk of severe (grade 3-4) gastrointestinal toxicity (OR = 3.12, P = 0.035 and OR = 6.99, P = 0.01, respectively). In gene-gene interaction analysis, GSTM1 null-GSTP1 GG showed 4.2-fold higher risk of severe gastrointestinal toxicity (P = 0.014). GSTT1 null-GSTP1 AG reached statistical significance with a 3.9-fold higher risk of high grade gastrointestinal toxicity (P = 0.038).
CONCLUSIONS: Although no significant links were found between GST polymorphism and treatment response, null genotypes of GSTM1, GSTT1 and 'G' allele of GSTP1 bring a higher risk of severe gastrointestinal toxicity due to chemoradiation therapy in cervical cancer.

Zhong Z, Li H, Zhong H, et al.
A systematic review and meta-analyses of the relationship between glutathione S-transferase gene polymorphisms and renal cell carcinoma susceptibility.
BMC Med Genet. 2018; 19(1):98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Association of GSTM1- and GSTT1-null genotypes, GSTP1 A/G gene polymorphism with renal cell carcinoma (RCC) susceptibility was detected, and the relationship between the GSTM1/GSTT1-null genotype and clinical TNM stages of RCC was assessed, using meta-analysis method.
METHODS: Association investigations according to eligibility criteria were searched and identified from the databases of Cochrane Library, PubMed, and Embase from establishment time of databases to July 1, 2017, and eligible reports were analyzed by meta-analysis. 95% confidence intervals (CI) were also detected, and odds ratios (OR) was used to express the results for dichotomous data.
RESULTS: This meta-analysis indicated that there was no an association between GSTM1-null genotype, GSTT1-null genotype, GSTP1 A/G gene polymorphism and RCC risk in the overall population of Caucasians or Asians. The dual GSTM1-GSTT1-null genotype was also not associated with RCC in the overall population of Caucasians. Interestingly, there was an association between the dual GSTM1-GSTT1-null genotype and the susceptibility of RCC in Asians. Relationship of the GSTM1-null genotype with clinical TNM stage of RCC was not observed in the overall population of Asians or Caucasians. In this meta-analysis, no association between the GSTT1-null genotype and clinical TNM stage of RCC was observed in Caucasians or Asians. Interestingly, GSTT1-null genotype was detected to be associated with the clinical TNM stages in patients with RCC in the overall population.
CONCLUSION: The dual GSTM1-GSTT1-null genotype is detected to be associated with the onset of RCC in Asians, and there is an association between the GSTT1-null genotype and the clinical TNM stages in patients with RCC in the overall population.

Rajesh D, Balakrishna S, Azeem Mohiyuddin SM, et al.
GSTP1 c.341C>T gene polymorphism increases the risk of oral squamous cell carcinoma.
Mutat Res Genet Toxicol Environ Mutagen. 2018; 831:45-49 [PubMed] Related Publications
Glutathione S Transferases (GST) are anti-oxidant enzymes involved in detoxification of cellular and exogenous carcinogens and oxidative products of reactive oxygen species. Genetic polymorphisms can attenuate the detoxification capacity of GST and consequently increase the susceptibility to carcinogenesis. There are eight classes of GST enzymes of which pi subtype is the predominant form expressed in the oral mucosa. c.341C > T single nucleotide polymorphism (rs1138272) in GSTP1 gene, is a functional variation that reduces the enzymatic activity of GST pi. We carried out a 1:2 case-control study involving 270 individuals to determine the association of c.341C > T variation with the risk of oral squamous cell carcinoma. GSTP1 c.341C > T variation was genotyped by PCR-RFLP method. GST pi expression in the tumour sample was determined by immunohistochemistry. Tobacco consumption was the major risk factor among cancer patients. The odds ratio for the risk of oral squamous cell carcinoma in individuals with the minor allele was 4.5 (0.95 CI = 2.3-8.9; P = 0.000004). The genotype was found to follow dominant mode of inheritance (OR 4.4 [0.95 CI = 2.1-9.2]; P = 0.00006). Our results support the conclusion that c.341C > T variation in GSTP1 increases the risk of OSCC in patients habituated to tobacco consumption.

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