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

Autor(es)

Barquilha, Caroline N. ^{[1, 2]} ; Santos, Nilton J. ^{[1, 2]} ; Moncao, Caio C. D. ^{[1, 2]} ; Barbosa, Isabela C. ^{[1, 2]} ; Lima, Flavio O. ^[3] ; Justulin, Luis A. ^[2] ; Pertega-Gomes, Nelma ^[4] ; Felisbino, Sergio L. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Inst Biol, BR-13083862 Campinas, SP - Brazil

^[2] Sao Paulo State Univ, Inst Biosci, Dept Morphol, BR-18618689 Botucatu, SP - Brazil

^[3] Sao Paulo State Univ, Botucatu Med Sch, Dept Pathol, BR-18618687 Botucatu, SP - Brazil

^[4] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 - USA

• Tipo de documento: Artigo Científico
• Fonte: OXIDATIVE MEDICINE AND CELLULAR LONGEVITY; v. 2020, JAN 20 2020.
• Citações Web of Science: 0

Resumo

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; Pten(f/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. (AU)

• Processo FAPESP: 16/09532-3 - Câncer de próstata: alterações nos proteoglicanos da família Sindecan, na enzima de estresse oxidativo sulfiredoxina e na enzima quinase de ciclo celular MELK
• Beneficiário: Sérgio Luis Felisbino
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/26097-6 - Expressão da enzima Sulfiredoxina em dois modelos de camundongos knockouts para câncer de próstata e por células epiteliais prostáticas normais e tumorais em diferentes condições de cultura
• Beneficiário: Caroline Nascimento Barquilha
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 16/25945-6 - Câncer de próstata e estresse oxidativo: análise da expressão e do potencial terapêutico da enzima sulfiredoxina
• Beneficiário: Caroline Nascimento Barquilha
• Modalidade de apoio: Bolsas no Brasil - Mestrado