Abstract
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.
Highlights
The incidence of prostate cancer (PCa) has progressively increased in the western world, representing the second most prevalent cancer with the second highest mortality rate in men [1,2,3]
Antioxidant pathways play an important cytoprotective role in tumors by preventing treatment-induced apoptosis and conferring chemoresistance [41,42,43,44,45]. Since these tumor cells are highly dependent on antioxidant mechanisms [38, 40], we aimed to identify genes involved in oxidative stress homeostasis that can be therapeutically targeted for the treatment of PCa
Excluding those genes with no clinical relevance, and those which have already been associated with PCa, such as Ctsb, Gpx2, Idh1, and Nos2 [60,61,62,63,64,65,66], we selected the antioxidant enzyme Srxn1 that had a strong correlation with patient outcome and has no previous related functional studies in PCa
Summary
The incidence of prostate cancer (PCa) has progressively increased in the western world, representing the second most prevalent cancer with the second highest mortality rate in men [1,2,3]. The chances of curing PCa are high, but more advanced PCa develops resistance to androgen deprivation therapies [7, 8]. These tumors are referred to as “castration-resistant PCa,” are highly heterogeneous in their molecular alterations [9,10,11], and are resistant to available therapies [12,13,14]. It is crucial to identify new therapeutic targets and additional approaches to cure or at least increase the survival of patients with advanced PCa [15, 16]
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