Targeting GSTM3 for therapeutic potential in advanced prostate cancer

Prostate cancer (PCa) represents one of the most prevalent malignancies among men worldwide. When diagnosed at an early, localized stage, PCa is generally associated with a favorable prognosis and is often amenable to curative treatment modalities. However, the management of advanced PCa continues to pose significant therapeutic challenges despite the availability of conventional treatment modalities such as androgen deprivation therapy (ADT), salvage radiotherapy, and systemic chemotherapy. This underscores the urgent need to identify novel molecular targets that can enhance therapeutic efficacy and improve clinical outcomes in advanced disease. Glutathione S-transferase mu 3 (GSTM3), a detoxification enzyme involved in redox regulation and cellular homeostasis, has emerged as a potential contributor to PCa progression. The present study investigates the expression profile and functional significance of GSTM3 in advanced PCa, with the aim of elucidating its role in disease pathobiology and therapeutic targeting. GSTM3 expression levels were analyzed using public datasets from GEO and UALCAN. Quantitative RT-PCR was employed to validate expression levels in DU-145 and PC-3 cell lines, as well as in tumorsphere models. GSTM3 silencing was achieved using siRNA. ROS and mtMP were measured using H2DCFDA and Rhodamine assays, respectively. The impact on the cell cycle was assessed via PI staining, apoptosis and necrosis were evaluated using flow cytometry. Analysis of previous datasets and current experimental data revealed that GSTM3 was overexpressed in advanced PCa cells. Tumorsphere models exhibited even higher GSTM3 expression compared to conventional cell lines. In GSTM3-silenced cells, mtMP increased, while ROS levels showed a slight decrease. Silencing GSTM3 also led to cell cycle arrest in the G0/G1 phase, with a significant increase in necrosis and a modest rise in apoptosis. Our findings demonstrate the functional role of GSTM3 in advanced PCa, highlighting its potential as a therapeutic target. The consistent data suggest that targeting GSTM3 could offer new avenues for PCa treatment.