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Anti-Cancer Effects and Tumor Marker Role of Glutathione S-Transferase Mu 5 in Human Bladder Cancer.

ABSTRACT: Our previous study demonstrated that the glutathione S-transferase Mu 5 (GSTM5) gene is highly CpG-methylated in bladder cancer cells and that demethylation by 5-aza-dC activates GSTM5 gene expression. The aim of the present study was to investigate the role of GSTM5 in bladder cancer. The levels of GSTM5 gene expression and DNA methylation were analyzed in patients with bladder cancer, and functional studies of GSTM5 were conducted using GSTM5 overexpression in cultured bladder cancer cells. Clinical analysis revealed that the GSTM5 mRNA expression was lower in bladder cancer tissues than in normal tissues and that the level of GSTM5 DNA methylation was higher in bladder cancer tissues than in normal urine pellets. Overexpression of GSTM5 decreased cell proliferation, migration and colony formation capacity. Glutathione (GSH) assay results indicated that cellular GSH concentration was decreased by GSTM5 expression and that GSH supplementation reversed the decrease in proliferation and migration of cells overexpressing GSTM5. By contrast, a GSH synthesis inhibitor significantly decreased 5637 cell GSH levels, survival and migration. Furthermore, GSTM5 overexpression inhibited the adhesion of cells to the extracellular matrix protein fibronectin. To elucidate the effect of GSTM5 on anticancer drugs used to treat bladder cancer, cellular viability was compared between cells with or without GSTM5 overexpression. GSTM5-overexpressed cells showed no significant change in the cytotoxicity of cisplatin or mitomycin C in 5637, RT4 and BFTC 905 cells. Though a degree of resistance to doxorubicin was noted in 5637 cells overexpressing GSTM5, no such resistance was observed in RT4 and BFTC 905 cells. In summary, GSTM5 plays a tumor suppressor role in bladder cancer cells without significantly affecting chemoresistance to cisplatin and mitomycin C, and the cellular GSH levels highlight a key mechanism underlying the cancer inhibition effect of GSTM5. These findings suggest that low gene expression and high DNA methylation levels of GSTM5 may act as tumor markers for bladder cancer.

SUBMITTER: Jou YC

PROVIDER: S-EPMC8002531 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Pancreatic cancer (PC) is a lethal malignancy with an extremely unfavorable 5-year survival rate and a high mortality rate. Glutathione S-transferase mu-3 (GSTM3) has been shown to exert different functions in the progression and development of various cancers, except for PC. This study aimed to explore the role of GSTM3 in the malignant behavior and metabolic aspects of PC, its clinical significance, and its possible molecular mechanism in pancreatic cancer. Methods: Tumor microarrays of pancreatic ductal adenocarcinoma (PDAC) were used to evaluate the clinicopathological variables and GSTM3 expression by immunohistochemical staining. Kaplan-Meier survival and Cox regression analyses were further performed to assess the prognosis. The effect of GSTM3 on PC aggressiveness was detected using overexpressing and silencing transfection methods. Western blot, RT-qPCR, CCK-8, and cell cycle assay were applied to evaluate the expression level and proliferation. A xenograft animal model was assessed. Reactive oxygen species (ROS) were measured using the laser confocal scanner and glycolysis was detected using an Agilent Seahorse kit. RNA sequencing was used to assess the underlying mechanism and the signaling pathway involved. Results: GSTM3 was relatively poorly expressed in PDAC tissues compared to para-tumoral tissues and a high level of GSTM3 indicated good overall survival. Functionally, overexpression of GSTM3 could significantly inhibit cell proliferation by delaying the G0/G1 transition, whereas the opposite results were found in the GSTM3 downregulation group. In addition, xenograft animal models further confirmed the effect on proliferation. Moreover, silencing of GSTM3 induced ROS accumulation and promoted glycolysis in PC, indicating its tumor suppressive effect, and vice versa when GSTM3 was upregulated. Finally, RNA sequencing results demonstrated that GSTM3 facilitates anti-tumorigenicity partly via the JAK-STAT signaling pathway in PC. Conclusion: GSTM3 inhibited tumor progression and altered the metabolic pattern in PC. This may be a potential predictive biomarker in PC and a prospective therapeutic target.

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Anti-Cancer Effects and Tumor Marker Role of Glutathione S-Transferase Mu 5 in Human Bladder Cancer.

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