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Deleterious effects of SNPs found in genes encoding transcriptional factors, as well as antioxidant and detoxification enzymes, are disputable; however, their functional significance seems to modify the risk for clear cell renal cell carcinoma (ccRCC) development and progression. We investigated the effect of specific Nrf2, SOD2, GPX1 gene variants and GSTP1ABCD haplotype on ccRCC risk and prognosis and evaluated the association between GSTP1 and regulatory (JNK1/2) and executor (caspase-3) apoptotic molecule expression in ccRCC tissue samples and the presence of GSTP1 : JNK1/2 protein : protein interactions. Genotyping was performed in 223 ccRCC patients and 336 matched controls by PCR-CTTP and qPCR. Protein expression was analyzed using immunoblot, while the existence of GSTP1 : JNK1 protein : protein interactions was investigated by immunoprecipitation experiments. An increased risk of ccRCC development was found among carriers of variant genotypes of both SOD2 rs4880 and GSTP1 rs1695 polymorphisms. Nrf2 rs6721961 genetic polymorphism in combination with both rs4880 and rs1695 showed higher ccRCC risk as well. Haplotype analysis revealed significant risk of ccRCC development in carriers of the GSTP1C haplotype. Furthermore, GSTP1 variant forms seem to affect the overall survival in ccRCC patients, and the proposed molecular mechanism underlying the GSTP1 prognostic role might be the presence of GSTP1 : JNK1/2 protein : protein interactions.
Smiljana Mihailovic; Vesna Coric; Tanja Radic; Ana Savic Radojevic; Marija Matic; Dejan Dragicevic; Milica Djokic; Vladimir Vasic; Zoran Dzamic; Tatjana Simic; Jovan Hadzi-Djokic; Marija Pljesa Ercegovac. The Association of Polymorphisms in Nrf2 and Genes Involved in Redox Homeostasis in the Development and Progression of Clear Cell Renal Cell Carcinoma. Oxidative Medicine and Cellular Longevity 2021, 2021, 1 -15.
AMA StyleSmiljana Mihailovic, Vesna Coric, Tanja Radic, Ana Savic Radojevic, Marija Matic, Dejan Dragicevic, Milica Djokic, Vladimir Vasic, Zoran Dzamic, Tatjana Simic, Jovan Hadzi-Djokic, Marija Pljesa Ercegovac. The Association of Polymorphisms in Nrf2 and Genes Involved in Redox Homeostasis in the Development and Progression of Clear Cell Renal Cell Carcinoma. Oxidative Medicine and Cellular Longevity. 2021; 2021 ():1-15.
Chicago/Turabian StyleSmiljana Mihailovic; Vesna Coric; Tanja Radic; Ana Savic Radojevic; Marija Matic; Dejan Dragicevic; Milica Djokic; Vladimir Vasic; Zoran Dzamic; Tatjana Simic; Jovan Hadzi-Djokic; Marija Pljesa Ercegovac. 2021. "The Association of Polymorphisms in Nrf2 and Genes Involved in Redox Homeostasis in the Development and Progression of Clear Cell Renal Cell Carcinoma." Oxidative Medicine and Cellular Longevity 2021, no. : 1-15.
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful biomarkers for detection in its early stages, when surgery can be curative. We have previously described a promising biomarker panel (LYVE1, REG1A, and TFF1) for earlier detection of PDAC in urine. Here, we aimed to establish the accuracy of an improved panel, including REG1B instead of REG1A, and an algorithm for data interpretation, the PancRISK score, in additional retrospectively collected urine specimens. We also assessed the complementarity of this panel with CA19-9 and explored the daily variation and stability of the biomarkers and their performance in common urinary tract cancers. Methods and findings Clinical specimens were obtained from multiple centres: Barts Pancreas Tissue Bank, University College London, University of Liverpool, Spanish National Cancer Research Center, Cambridge University Hospital, and University of Belgrade. The biomarker panel was assayed on 590 urine specimens: 183 control samples, 208 benign hepatobiliary disease samples (of which 119 were chronic pancreatitis), and 199 PDAC samples (102 stage I–II and 97 stage III–IV); 50.7% were from female individuals. PDAC samples were collected from patients before treatment. The samples were assayed using commercially available ELISAs. Statistical analyses were performed using non-parametric Kruskal–Wallis tests adjusted for multiple comparisons, and multiple logistic regression. Training and validation datasets for controls and PDAC samples were obtained after random division of the whole available dataset in a 1:1 ratio. The substitution of REG1A with REG1B enhanced the performance of the panel to detect resectable PDAC. In a comparison of controls and PDAC stage I–II samples, the areas under the receiver operating characteristic curve (AUCs) increased from 0.900 (95% CI 0.843–0.957) and 0.926 (95% CI 0.843–1.000) in the training (50% of the dataset) and validation sets, respectively, to 0.936 in both the training (95% CI 0.903–0.969) and the validation (95% CI 0.888–0.984) datasets for the new panel including REG1B. This improved panel showed both sensitivity (SN) and specificity (SP) to be >85%. Plasma CA19-9 enhanced the performance of this panel in discriminating PDAC I–II patients from controls, with AUC = 0.992 (95% CI 0.983–1.000), SN = 0.963 (95% CI 0.913–1.000), and SP = 0.967 (95% CI 0.924–1.000). We demonstrate that the biomarkers do not show significant daily variation, and that they are stable for up to 5 days at room temperature. The main limitation of our study is the low number of stage I–IIA PDAC samples (n = 27) and lack of samples from individuals with hereditary predisposition to PDAC, for which specimens collected from control individuals were used as a proxy. Conclusions We have successfully validated our urinary biomarker panel, which was improved by substituting REG1A with REG1B. At a pre-selected cutoff of >80% SN and SP for the affiliated PancRISK score, we demonstrate a clinically applicable risk stratification tool with a binary output for risk of developing PDAC (‘elevated’ or ‘normal’). PancRISK provides a step towards precision surveillance for PDAC patients, which we will test in a prospective clinical study, UroPanc.
Silvana Debernardi; Harrison O’Brien; Asma S. Algahmdi; Nuria Malats; Grant D. Stewart; Marija Plješa-Ercegovac; Eithne Costello; William Greenhalf; Amina Saad; Rhiannon Roberts; Alexander Ney; Stephen P. Pereira; Hemant M. Kocher; Stephen Duffy; Oleg Blyuss; Tatjana Crnogorac-Jurcevic. A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case–control study. PLOS Medicine 2020, 17, e1003489 .
AMA StyleSilvana Debernardi, Harrison O’Brien, Asma S. Algahmdi, Nuria Malats, Grant D. Stewart, Marija Plješa-Ercegovac, Eithne Costello, William Greenhalf, Amina Saad, Rhiannon Roberts, Alexander Ney, Stephen P. Pereira, Hemant M. Kocher, Stephen Duffy, Oleg Blyuss, Tatjana Crnogorac-Jurcevic. A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case–control study. PLOS Medicine. 2020; 17 (12):e1003489.
Chicago/Turabian StyleSilvana Debernardi; Harrison O’Brien; Asma S. Algahmdi; Nuria Malats; Grant D. Stewart; Marija Plješa-Ercegovac; Eithne Costello; William Greenhalf; Amina Saad; Rhiannon Roberts; Alexander Ney; Stephen P. Pereira; Hemant M. Kocher; Stephen Duffy; Oleg Blyuss; Tatjana Crnogorac-Jurcevic. 2020. "A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case–control study." PLOS Medicine 17, no. 12: e1003489.
Disturbed redox homeostasis represents a hallmark of cancer phenotypes, affecting cellular metabolism and redox signaling. Since reactive oxygen and nitrogen species (ROS/RNS) are involved in regulation of proliferation and apoptosis, they may play a double-faced role in cancer, entailing protumorigenic and tumor-suppressing effects in early and later stages, respectively. In addition, ROS and RNS impact the activity and communication of all tumor constituents, mediating their reprogramming from anti- to protumorigenic phenotypes, and vice versa. An important role in this dichotomic action is played by the variable amounts of O2 in the tumor microenvironment, which dictates the ultimate outcome of the influence of ROS/RNS on carcinogenesis. Moreover, ROS/RNS levels remarkably influence the cancer response to therapy. The relevance of ROS/RNS signaling in solid tumors is witnessed by the emergence of novel targeted treatments of solid tumors with compounds that target ROS/RNS action and production, such as tyrosine kinase inhibitors and monoclonal antibodies, which might contribute to the complexity of redox regulation in cancer. Prospectively, the dual role of ROS/RNS in the different stages of tumorigenesis through different impact on oxidation and nitrosylation may also allow development of tailored diagnostic and therapeutic approaches.
Sanja Mijatović; Ana Savić-Radojević; Marija Plješa-Ercegovac; Tatjana Simić; Ferdinando Nicoletti; Danijela Maksimović-Ivanić. The Double-Faced Role of Nitric Oxide and Reactive Oxygen Species in Solid Tumors. Antioxidants 2020, 9, 374 .
AMA StyleSanja Mijatović, Ana Savić-Radojević, Marija Plješa-Ercegovac, Tatjana Simić, Ferdinando Nicoletti, Danijela Maksimović-Ivanić. The Double-Faced Role of Nitric Oxide and Reactive Oxygen Species in Solid Tumors. Antioxidants. 2020; 9 (5):374.
Chicago/Turabian StyleSanja Mijatović; Ana Savić-Radojević; Marija Plješa-Ercegovac; Tatjana Simić; Ferdinando Nicoletti; Danijela Maksimović-Ivanić. 2020. "The Double-Faced Role of Nitric Oxide and Reactive Oxygen Species in Solid Tumors." Antioxidants 9, no. 5: 374.
Background and Objectives: One of the most frequent genetic alterations reported to date in prostate cancer (PC) is aberrant methylation of glutathione transferase P1 (GSTP1). Taking into consideration the involvement of oxidative stress in PC pathogenesis and recent advances in scientific understanding of the role of GSTP1*Ala114Val rs1138272 polymorphism in carcinogenesis, we hypothesized that this single-nucleotide polymorphism (SNP) influences the risk of PC independently of, or in combination with, other GST polymorphisms, including GSTP1*IIe105Val rs1695 or GSTM1 and GSTT1 deletion polymorphisms. Materials and Methods: Genotyping was performed in 237 PC cases and in 236 age-matched controls by multiplex polymerase chain reaction (PCR) for deletion of GST polymorphisms and by quantitative PCR for SNPs. Results: We found that carriers of either GSTP1*Val (rs1138272) or GSTP1*Val (rs1695) variant alleles had a PC risk compared to individuals with both referent alleles (OR = 4.93, 95%CI: 2.89–8.40, p < 0.001 and OR = 1.8, 95%CI: 1.19–2.73, p = 0.006, respectively). Additionally, in a haplotype analysis we found that individuals with GSTP1*C haplotype, represented by both variant alleles (GSTP1*Val rs1695 + GSTP1*Val rs1138272), had a 5.46 times higher risk of PC development compared to individuals with the most frequent haplotype (95%CI = 2.56–11.65, p < 0.001), suggesting a potential role of those variants in PC susceptibility. A regression analysis on the number of risk-associated alleles per individual (GSTM1*active, GSTT1*null, GSTP1*Val rs1695 and GSTP1*Val rs1138272) showed a significant increase in the risk of developing PC, from 3.65-fold in carriers of two risk alleles (95%CI = 1.55–8.61, p = 0.003) to an approximately 12-fold increase in carriers of all four risk alleles (95%CI = 3.05–44.93, p < 0.001). Conclusion: Prostate cancer may be influenced by multiple glutathione transferase (GST) polymorphic genes, especially GSTP1, highlighting the role of gene–gene interactions in human susceptibility to this cancer.
Veljko Santric; Milica Djokic; Sonja Suvakov; Marija Pljesa-Ercegovac; Marina Nikitovic; Tanja Radic; Miodrag Acimovic; Vesna Stankovic; Uros Bumbasirevic; Bogomir Milojevic; Uros Babic; Zoran Dzamic; Tatjana Simic; Dejan Dragicevic; Ana Savic-Radojevic. GSTP1 rs1138272 Polymorphism Affects Prostate Cancer Risk. Medicina 2020, 56, 128 .
AMA StyleVeljko Santric, Milica Djokic, Sonja Suvakov, Marija Pljesa-Ercegovac, Marina Nikitovic, Tanja Radic, Miodrag Acimovic, Vesna Stankovic, Uros Bumbasirevic, Bogomir Milojevic, Uros Babic, Zoran Dzamic, Tatjana Simic, Dejan Dragicevic, Ana Savic-Radojevic. GSTP1 rs1138272 Polymorphism Affects Prostate Cancer Risk. Medicina. 2020; 56 (3):128.
Chicago/Turabian StyleVeljko Santric; Milica Djokic; Sonja Suvakov; Marija Pljesa-Ercegovac; Marina Nikitovic; Tanja Radic; Miodrag Acimovic; Vesna Stankovic; Uros Bumbasirevic; Bogomir Milojevic; Uros Babic; Zoran Dzamic; Tatjana Simic; Dejan Dragicevic; Ana Savic-Radojevic. 2020. "GSTP1 rs1138272 Polymorphism Affects Prostate Cancer Risk." Medicina 56, no. 3: 128.
Omega class glutathione transferases, GSTO1-1 and GSTO2-2, exhibit different activities involved in regulation of inflammation, apoptosis and redox homeostasis. We investigated the the prognostic significance of GSTO1 (rs4925) and GSTO2 (rs156697 and rs2297235) polymorphisms in clear cell renal cell carcinoma (ccRCC) patients. GSTO1-1 and GSTO2-2 expression and phosphorylation status of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ /mammalian target of rapamycin (mTOR) and Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathways in non-tumor and tumor ccRCC tissue, as well as possible association of GSTO1-1 with signaling molecules were also assessed. GSTO genotyping was performed by quantitative PCR in 228 ccRCC patients, while expression and immunoprecipitation were analyzed by Western blot in 30 tissue specimens. Shorter survival in male carriers of GSTO1*C/C wild-type genotype compared to the carriers of at least one variant allele was demonstrated (p = 0.049). GSTO1*C/C genotype independently predicted higher risk of overall mortality among male ccRCC patients (p = 0.037). Increased expression of GSTO1-1 and GSTO2-2 was demonstrated in tumor compared to corresponding non-tumor tissue (p = 0.002, p = 0.007, respectively), while GSTO1 expression was correlated with interleukin-1β (IL-1β)/pro-interleukin-1β (pro-IL-1β) ratio (r = 0.260, p = 0.350). Interaction of GSTO1 with downstream effectors of investigated pathways was shown in ccRCC tumor tissue. This study demonstrated significant prognostic role of GSTO1 polymorphism in ccRCC. Up-regulated GSTO1-1 and GSTO2-2 in tumor tissue might contribute to aberrant ccRCC redox homeostasis.
Tanja Radic; Vesna Coric; Zoran Bukumiric; Marija Pljesa-Ercegovac; Tatjana Djukic; Natasa Avramovic; Marija Matic; Smiljana Mihailovic; Dejan Dragicevic; Zoran Dzamic; Tatjana Simic; Ana Savic-Radojevic. GSTO1*CC Genotype (rs4925) Predicts Shorter Survival in Clear Cell Renal Cell Carcinoma Male Patients. Cancers 2019, 11, 2038 .
AMA StyleTanja Radic, Vesna Coric, Zoran Bukumiric, Marija Pljesa-Ercegovac, Tatjana Djukic, Natasa Avramovic, Marija Matic, Smiljana Mihailovic, Dejan Dragicevic, Zoran Dzamic, Tatjana Simic, Ana Savic-Radojevic. GSTO1*CC Genotype (rs4925) Predicts Shorter Survival in Clear Cell Renal Cell Carcinoma Male Patients. Cancers. 2019; 11 (12):2038.
Chicago/Turabian StyleTanja Radic; Vesna Coric; Zoran Bukumiric; Marija Pljesa-Ercegovac; Tatjana Djukic; Natasa Avramovic; Marija Matic; Smiljana Mihailovic; Dejan Dragicevic; Zoran Dzamic; Tatjana Simic; Ana Savic-Radojevic. 2019. "GSTO1*CC Genotype (rs4925) Predicts Shorter Survival in Clear Cell Renal Cell Carcinoma Male Patients." Cancers 11, no. 12: 2038.
Renal cell carcinoma (RCC) represents a group of histologically similar neoplasms with significant intratumor and intertumor genetic heterogeneity. Recognized risk factors for RCC development include smoking, hypertension, obesity, as well as von Hippel–Lindau (VHL) disease. Inactivation of VHL, deregulated nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) pathway, and altered redox homeostasis, together with changes in glutathione transferase (GST) profile, are considered as important contributing factors in RCC development and progression. Although the available results of both gene–gene and gene–environment analysis are quite heterogeneous, they clearly indicate that certain GST genotypes may play a role as risk modifiers, either individually or in combination with other Phase I or Phase II gene polymorphisms, as well as in subjects exposed to relevant substrates. Seemingly, GST genotyping could identify individuals with impaired detoxification in renal parenchyma that are at higher risk of developing RCC. In addition to well established roles of GSTs in conjugation and biotransformation of xenobiotics, GSTs have emerged as significant regulators of pathways determining cell proliferation and survival. Indeed, there are evidence in favor of GST significance, not only in terms of risk for RCC development, but also with respect to progression and prognosis. So far, GSTM1‐active genotype was confirmed to be an independent predictor of higher risk of overall mortality. Therefore, it is reasonable to assume that certain GST variants may assist in individual RCC risk assessment, as well as postoperative prognosis. Even more, GST profiling might contribute to development of personalized targeted therapy in RCC patients.
Marija Pljesa‐Ercegovac; Ana Savic‐Radojevic; Vesna Coric; Tanja Radic; Tatjana Simic. Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma. BioFactors 2019, 46, 229 -238.
AMA StyleMarija Pljesa‐Ercegovac, Ana Savic‐Radojevic, Vesna Coric, Tanja Radic, Tatjana Simic. Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma. BioFactors. 2019; 46 (2):229-238.
Chicago/Turabian StyleMarija Pljesa‐Ercegovac; Ana Savic‐Radojevic; Vesna Coric; Tanja Radic; Tatjana Simic. 2019. "Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma." BioFactors 46, no. 2: 229-238.
Background and Objectives: Experimental data show that superoxide dismutase 2 (SOD2) is involved in ochratoxin (OTA)-induced nephrotoxicity, whereas clinical data indicate the role of SOD2 rs4880 or glutathione peroxidase 1 (GPX1) rs1050450 polymorphisms in end-stage renal disease and urothelial carcinoma risk, known to be the major complications of Balkan endemic nephropathy (BEN). Therefore, we hypothesized that SOD2 and GPX1 gene polymorphisms would influence the risk of BEN and its associated tumors. Materials and Methods: The study was conducted in 207 BEN patients and 86 controls from endemic areas. Results: Individuals with both copies of variant SOD2 allele, known for lower mitochondrial antioxidant protection, are at a significantly higher BEN risk (OR = 2.6, p = 0.021). No association was observed between GPX1 gene polymorphism and BEN risk. Combining SOD2 and GPX1 genotypes did not alter the risk of BEN development. Regarding the risk of urothelial tumors in BEN patients, none of the polymorphisms studied was significantly associated with the risk of these tumors. Conclusions: Polymorphism in SOD2 rs4880 gene affects the risk of BEN development. Hence, SOD2 genotyping could, together with a panel of other enzymes, be used as a biomarker of susceptibility in BEN areas.
Biljana Dragicevic; Sonja Suvakov; Djurdja Jerotic; Zorica Reljic; Ljubica Djukanovic; Ivanka Zelen; Marija Pljesa-Ercegovac; Ana Savic-Radojevic; Tatjana Simic; Dejan Dragicevic; Marija Matic. Association of SOD2 (rs4880) and GPX1 (rs1050450) Gene Polymorphisms with Risk of Balkan Endemic Nephropathy and its Related Tumors. Medicina 2019, 55, 435 .
AMA StyleBiljana Dragicevic, Sonja Suvakov, Djurdja Jerotic, Zorica Reljic, Ljubica Djukanovic, Ivanka Zelen, Marija Pljesa-Ercegovac, Ana Savic-Radojevic, Tatjana Simic, Dejan Dragicevic, Marija Matic. Association of SOD2 (rs4880) and GPX1 (rs1050450) Gene Polymorphisms with Risk of Balkan Endemic Nephropathy and its Related Tumors. Medicina. 2019; 55 (8):435.
Chicago/Turabian StyleBiljana Dragicevic; Sonja Suvakov; Djurdja Jerotic; Zorica Reljic; Ljubica Djukanovic; Ivanka Zelen; Marija Pljesa-Ercegovac; Ana Savic-Radojevic; Tatjana Simic; Dejan Dragicevic; Marija Matic. 2019. "Association of SOD2 (rs4880) and GPX1 (rs1050450) Gene Polymorphisms with Risk of Balkan Endemic Nephropathy and its Related Tumors." Medicina 55, no. 8: 435.
The oxidative stress response via Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) interlinks inflammation- and metabolism-related pathways in chronic kidney disease. We assessed the association between polymorphisms in Nrf2, superoxide dismutase (SOD2), glutathione peroxidase (GPX1), and the risk of end-stage renal disease (ESRD). The modifying effect of these polymorphisms on both oxidative phenotype and ESRD prognosis, both independently and/or in combination with the glutathione S-transferase M1 (GSTM1) deletion polymorphism, was further analyzed. Polymorphisms in Nrf2 (rs6721961), SOD2 (rs4880), GPX1 (rs1050450), and GSTM1 were determined by PCR in 256 ESRD patients undergoing hemodialysis and 374 controls. Byproducts of oxidative stress were analyzed spectrophotometically or by ELISA. Time-to-event modeling was performed to evaluate overall survival and cardiovascular survival. The SOD2 Val/Val genotype increased ESRD risk (OR = 2.01, p = 0.002), which was even higher in combination with the GPX1 Leu/Leu genotype (OR = 3.27, p = 0.019). Polymorphism in SOD2 also showed an effect on oxidative phenotypes. Overall survival in ESRD patients was dependent on a combination of the Nrf2 (C/C) and GPX1 (Leu/Leu) genotypes in addition to a patients’ age and GSTM1 polymorphism. Similarly, the GPX1 (Leu/Leu) genotype contributed to longer cardiovascular survival. Conclusions: Our results show that SOD2, GPX1, and Nrf2 polymorphisms are associated with ESRD development and can predict survival.
Djurdja Jerotic; Marija Matic; Sonja Suvakov; Katarina Vucicevic; Tatjana Damjanovic; Ana Savic-Radojevic; Marija Pljesa-Ercegovac; Vesna Coric; Aleksandra Stefanovic; Jasmina Ivanisevic; Zorana Jelic-Ivanovic; Lana McClements; Nada Dimkovic; Tatjana Simic. Association of Nrf2, SOD2 and GPX1 Polymorphisms with Biomarkers of Oxidative Distress and Survival in End-Stage Renal Disease Patients. Toxins 2019, 11, 431 .
AMA StyleDjurdja Jerotic, Marija Matic, Sonja Suvakov, Katarina Vucicevic, Tatjana Damjanovic, Ana Savic-Radojevic, Marija Pljesa-Ercegovac, Vesna Coric, Aleksandra Stefanovic, Jasmina Ivanisevic, Zorana Jelic-Ivanovic, Lana McClements, Nada Dimkovic, Tatjana Simic. Association of Nrf2, SOD2 and GPX1 Polymorphisms with Biomarkers of Oxidative Distress and Survival in End-Stage Renal Disease Patients. Toxins. 2019; 11 (7):431.
Chicago/Turabian StyleDjurdja Jerotic; Marija Matic; Sonja Suvakov; Katarina Vucicevic; Tatjana Damjanovic; Ana Savic-Radojevic; Marija Pljesa-Ercegovac; Vesna Coric; Aleksandra Stefanovic; Jasmina Ivanisevic; Zorana Jelic-Ivanovic; Lana McClements; Nada Dimkovic; Tatjana Simic. 2019. "Association of Nrf2, SOD2 and GPX1 Polymorphisms with Biomarkers of Oxidative Distress and Survival in End-Stage Renal Disease Patients." Toxins 11, no. 7: 431.
Multifunctional enzymes glutathione transferases (GSTs) are involved in the development of chemoresistance, thus representing a promising target for a novel approach in cancer treatment. This superfamily of polymorphic enzymes exhibits extraordinary substrate promiscuity responsible for detoxification of numerous conventional chemotherapeutics, at the same time regulating signaling pathways involved in cell proliferation and apoptosis. In addition to upregulated GST expression, different cancer cell types have a unique GST signature, enabling targeted selectivity for isoenzyme specific inhibitors and pro-drugs. As a result of extensive research, certain GST inhibitors are already tested in clinical trials. Catalytic properties of GST isoenzymes are also exploited in bio-activation of specific pro-drugs, enabling their targeted accumulation in cancer cells with upregulated expression of the appropriate GST isoenzyme. Moreover, the latest approach to increase specificity in treatment of solid tumors is development of GST pro-drugs that are derivatives of conventional anti-cancer drugs. A future perspective is based on the design of new drugs, which would selectively target GST overexpressing cancers more prone to developing chemoresistance, while decreasing side effects in off-target cells.
Marija Pljesa-Ercegovac; Ana Savic-Radojevic; Marija Matic; Vesna Coric; Tatjana Djukic; Tanja Radic; Tatjana Simic. Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors. International Journal of Molecular Sciences 2018, 19, 3785 .
AMA StyleMarija Pljesa-Ercegovac, Ana Savic-Radojevic, Marija Matic, Vesna Coric, Tatjana Djukic, Tanja Radic, Tatjana Simic. Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors. International Journal of Molecular Sciences. 2018; 19 (12):3785.
Chicago/Turabian StyleMarija Pljesa-Ercegovac; Ana Savic-Radojevic; Marija Matic; Vesna Coric; Tatjana Djukic; Tanja Radic; Tatjana Simic. 2018. "Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors." International Journal of Molecular Sciences 19, no. 12: 3785.
•Patients with clear cell RCC and GSTM1-null genotype have longer overall survival.•GSTM1-active genotype is an independent predictor of higher ccRCC mortality risk.•ASK1:GSTM1 interaction might be mechanism underlying GSTs’ prognostic role in ccRCC. AbstractPurposeOwing to dual functionality of cytosolic glutathione S-transferases (GSTs), they might affect both the development and the progression of renal cell carcinoma (RCC). However, the data on the prognostic value of GST polymorphism in patients with RCC are scarce. Hence, we evaluated the effect of GST gene variants on both the risk of RCC development and the postoperative prognosis in patients with clear cell RCC (ccRCC).MethodsGST genotypes were determined in 305 patients with RCC and 326 matched controls, whereas the overall survival was evaluated in patients with ccRCC only. The presence of GSTM1:ASK1 protein-protein interaction in ccRCC tissue samples was analyzed by methods of immunoprecipitation and immunoblot.ResultsWe noted an increased risk of RCC development in carriers of GSTM1-null and GSTP1-variant genotype (P<0.05). On the contrary, survival analysis indicated shorter overall survival for patients with ccRCC with GSTM1-active genotype (P = 0.026). Furthermore, patients with ccRCC with GSTM1-active genotype had significantly higher hazard ratio (P<0.05), in analyzed regression models, compared with the carriers of GSTM1-null genotype. Finally, the presence of GSTM1:ASK1 protein-protein interaction was found in all RCC tissue samples studied.ConclusionsCarriers of GSTM1-null and GSTP1-variant genotypes are in increased risk of RCC development. On the contrary, GSTM1-null genotype is associated with favorable postoperative prognosis in ccRCC. The possible molecular mechanism underlying the role of GSTM1 protein in RCC progression might be the presence of GSTM1:ASK1 protein-protein interaction. Hence, determination of GSTM1-genotype might serve as a valuable indicator in both RCC risk assessment and postoperative prognosis. PurposeOwing to dual functionality of cytosolic glutathione S-transferases (GSTs), they might affect both the development and the progression of renal cell carcinoma (RCC). However, the data on the prognostic value of GST polymorphism in patients with RCC are scarce. Hence, we evaluated the effect of GST gene variants on both the risk of RCC development and the postoperative prognosis in patients with clear cell RCC (ccRCC). Owing to dual functionality of cytosolic glutathione S-transferases (GSTs), they might affect both the development and the progression of renal cell carcinoma (RCC). However, the data on the prognostic value of GST polymorphism in patients with RCC are scarce. Hence, we evaluated the effect of GST gene variants on both the risk of RCC development and the postoperative prognosis in patients with clear cell RCC (ccRCC). MethodsGST genotypes were determined in 305 patients with RCC and 326 matched controls, whereas the overall survival was evaluated in patients with ccRCC only. The presence of GSTM1:ASK1 protein-protein interaction in ccRCC tissue samples was analyzed by methods of immunoprecipitation and immunoblot. GST genotypes were determined in 305 patients with RCC and 326 matched controls, whereas the overall survival was evaluated in patients with ccRCC only. The presence of GSTM1:ASK1 protein-protein interaction in ccRCC tissue samples was analyzed by methods of immunoprecipitation and immunoblot. ResultsWe noted an increased risk of RCC development in carriers of GSTM1-null and GSTP1-variant genotype (P<0.05). On the contrary, survival analysis indicated shorter overall survival for patients with ccRCC with GSTM1-active genotype (P = 0.026). Furthermore, patients with ccRCC with GSTM1-active genotype had significantly higher hazard ratio (P<0.05), in analyzed regression models, compared with the carriers of GSTM1-null genotype. Finally, the presence of GSTM1:ASK1 protein-protein interaction was found in all RCC tissue samples studied. We noted an increased risk of RCC development in carriers of GSTM1-null and GSTP1-variant genotype (P<0.05). On the contrary, survival analysis indicated shorter overall survival for patients with ccRCC with GSTM1-active genotype (P = 0.026). Furthermore, patients with ccRCC with GSTM1-active genotype had significantly higher hazard ratio (P<0.05), in analyzed regression models, compared with the carriers of GSTM1-null genotype. Finally, the presence of GSTM1:ASK1 protein-protein interaction was found in all RCC tissue samples studied. ConclusionsCarriers of GSTM1-null and GSTP1-variant genotypes are in increased risk of RCC development. On the contrary, GSTM1-null genotype is associated with favorable postoperative prognosis in ccRCC. The possible molecular mechanism underlying the role of GSTM1 protein in RCC progression might be the presence of GSTM1:ASK1 protein-protein interaction. Hence, determination of GSTM1-genotype might serve as a valuable indicator in both RCC risk assessment and postoperative prognosis. Carriers of GSTM1-null and GSTP1-variant genotypes are in increased risk of RCC development. On the contrary, GSTM1-null genotype is associated with favorable postoperative prognosis in ccRCC. The possible molecular mechanism underlying the role of GSTM1 protein in RCC progression might be the presence of GSTM1:ASK1 protein-protein interaction. Hence, determination of GSTM1-genotype might serve as a valuable indicator in both RCC risk assessment and postoperative prognosis.
Vesna M. Coric; Tatjana P. Simic; Tatjana D. Pekmezovic; Gordana M. Basta-Jovanovic; Ana R. Savic-Radojevic; Sanja M. Radojevic-Skodric; Marija G. Matic; Sonja R. Suvakov; Dejan P. Dragicevic; Tanja M. Radic; Zoran M. Dzamic; Marija S. Pljesa-Ercegovac. GSTM1 genotype is an independent prognostic factor in clear cell renal cell carcinoma. Urologic Oncology: Seminars and Original Investigations 2017, 35, 409 -417.
AMA StyleVesna M. Coric, Tatjana P. Simic, Tatjana D. Pekmezovic, Gordana M. Basta-Jovanovic, Ana R. Savic-Radojevic, Sanja M. Radojevic-Skodric, Marija G. Matic, Sonja R. Suvakov, Dejan P. Dragicevic, Tanja M. Radic, Zoran M. Dzamic, Marija S. Pljesa-Ercegovac. GSTM1 genotype is an independent prognostic factor in clear cell renal cell carcinoma. Urologic Oncology: Seminars and Original Investigations. 2017; 35 (6):409-417.
Chicago/Turabian StyleVesna M. Coric; Tatjana P. Simic; Tatjana D. Pekmezovic; Gordana M. Basta-Jovanovic; Ana R. Savic-Radojevic; Sanja M. Radojevic-Skodric; Marija G. Matic; Sonja R. Suvakov; Dejan P. Dragicevic; Tanja M. Radic; Zoran M. Dzamic; Marija S. Pljesa-Ercegovac. 2017. "GSTM1 genotype is an independent prognostic factor in clear cell renal cell carcinoma." Urologic Oncology: Seminars and Original Investigations 35, no. 6: 409-417.