Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

• Published in: Oxidative medicine and cellular longevity 2020, Vol.2020 (2020), p.1-12
• Main Authors: Felisbino, Sérgio Luis, Justulin, Luis A., Lima, Flávio O., Barbosa, Isabela C., Monção, Caio C. D., Santos, Nilton J., Barquilha, Caroline N., Pértega-Gomes, Nelma
• Format: Article
• Language: English
• Subjects: Analysis; Androgens; Animals; Antioxidants; Cancer; Care and treatment; Cell Line, Tumor; Cell Survival; Development and progression; Disease Progression; Enzymes; Ethics; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic engineering; Genetically modified organisms; Genomes; Genomics; Humans; Immunohistochemistry; Male; Medical prognosis; Medical research; Metastasis; Mice; Molecular Targeted Therapy; Mutation; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Oxidative stress; Oxidative Stress - genetics; Oxidoreductases Acting on Sulfur Group Donors - genetics; Oxidoreductases Acting on Sulfur Group Donors - metabolism; Prognosis; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Protein expression; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Survival Analysis; Tumors
• ISSN: 1942-0900; 1942-0994
• DOI: 10.1155/2020/2148562

The incidence of prostate cancer (PCa) is increasing, and it is currently the second most frequent cause of death by cancer in men. Despite advancements in cancer therapies, new therapeutic approaches are still needed for treatment-refractory advanced metastatic PCa. Cross-species analysis presents a robust strategy for the discovery of new potential therapeutic targets. This strategy involves the integration of genomic data from genetically engineered mouse models (GEMMs) and human PCa datasets. Considering the role of antioxidant pathways in tumor initiation and progression, we searched oxidative stress-related genes for a potential therapeutic target for PCa. First, we analyzed RNA-sequencing data from Pb-Cre4; Ptenf/f mice and discovered an increase in sulfiredoxin (Srxn1) mRNA expression in high-grade prostatic intraepithelial neoplasia (PIN), well-differentiated adenocarcinoma (medium-stage tumors), and poor-differentiated adenocarcinoma (advanced-stage prostate tumors). The increase of SRXN1 protein expression was confirmed by immunohistochemistry in mouse prostate tumor paraffin samples. Analyses of human databases and prostate tissue microarrays demonstrated that SRXN1 is overexpressed in a subset of high-grade prostate tumors and correlates with aggressive PCa with worse prognosis and decreased survival. Analyses in vitro showed that SRXN1 expression is also higher in most PCa cell lines compared to normal cell lines. Furthermore, siRNA-mediated downregulation of SRXN1 led to decreased viability of PCa cells LNCaP. In conclusion, we identified the antioxidant enzyme SRXN1 as a potential therapeutic target for PCa. Our results suggest that the use of specific SRXN1 inhibitors may be an effective strategy for the adjuvant treatment of castration-resistant PCa with SRXN1 overexpression.