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

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.

Hyperoxidation of Peroxiredoxins and Effects on Physiology of Drosophila

“…On the other hand, by reducing ROS and affecting apoptosis, Srx may favor the survival of cancerous cells and thereby contribute to carcinogenesis [ 48 ]. For instance, Srx underexpression can sensitize cancer cells to ER stress-induced cell death [ 49 ], increase apoptosis of tumor cells and thus decrease tumor cell proliferation, while the opposite effects have been observed in Srx overexpressors, which correlated with more aggressive cancers and poor prognosis [ 8 , 48 , 50 , 51 , 52 , 53 ].…”

Sulfiredoxin‐1 is a promising novel prognostic biomarker for hepatocellular carcinoma

“…16 It had been demonstrated as a critical player in cell proliferation, migration, and metastasis, 6 and its abnormal expression usually contributed to the poor survival. 15,[17][18][19] All these evidence revealed that SRXN1 functioned as an oncogene. Study had demonstrated SRXN1 and peroxiredoxin 1 (RRDX1) played a pivotal role in protecting the liver in ethanol-fed mice against oxidative injury by eliminating ROS.…”

“…Studies had shown that SRXN1 was overexpressed in multiple types of malignancies, including cervical cancer, 12 colorectal cancer, 13 skin cancer, 14 lung cancer, 15 and renal cell carcinoma 16 . It had been demonstrated as a critical player in cell proliferation, migration, and metastasis, 6 and its abnormal expression usually contributed to the poor survival 15,17‐19 …”

Targeting the Redox Landscape in Cancer Therapy

“…Overoxidation of the peroxidatic cysteine yields sulfinic or irreversible sulfonic acid, rendering PRDX inactive [206] ( Figure 2). Sulfinic acid in PRDX can be reduced to sulfenic acid by sulfiredoxin, an antioxidative enzyme that is explored as a potential drug target in cancer therapy [207][208][209]. Reversible sulfenic acid in PRDXs is reduced by the thiol-containing thioredoxin, which exists as a cytosolic (TXN1) and a mitochondrial version (TXN2).…”