EFFECTS OF CHEMICAL INHIBITION OF THE ANTIOXIDANT ENZYME SULFIREDOXIN ON PC-3 PROSTATE TUMOR CELL SPHEROIDS

• Grant number: 23/09886-3
• Support Opportunities: Scholarships in Brazil - Master
• Start date: March 01, 2024
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Sérgio Luis Felisbino
• Grantee: Micheli Canuto de Lima
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Currently, prostate cancer (PCa) is the second highest in incidence and the fifth leading cause of male death from cancer in the world. Despite advances in the diagnostic field, metastatic castration-resistant PCa remains incurable, with an overall 5-year survival rate of 30%. For this reason, new therapeutic approaches for mCRPC are still needed, searching for targets related or not to androgen receptor signaling. DNA-damage repair enzymes, immune cell response, celullar metabolism are promising targets, however special attention has been also given to oxidative stress related pathways. Recent studies by our research group have demonstrated overexpression of the antioxidant enzyme sulfiredoxin (SRXN1) in more advanced stages of PCa, correlated with worse prognosis and shorter patient survival. Our group also demonstrated that knockdown of SRXN1 expression in prostate tumor cells reduces their viability and migratory capacity, in addition to increasing their chemosensitivity to docetaxel. Given the above, the present work aims to deepen the studies of the effects of SRXN1 inhibition by a synthetic inhibitor, J14, on normal (PNT-2) and tumor (PC-3) prostate epithelial cells in 2D and 3D cell culture. After exposure to the J14 inhibitor, cell viability (2D and 3D), with and without combined exposure to docetaxel (2D); migratory capacity (2D); lipid peroxidation (3D), apoptosis and cell cycle analysis will be evaluated (3D), in addition to evaluation of off-targets by exposure of the inhibitor in PC-3 Knockout cells (SRXN1) (2D). Finally, the expression of oxidative stress pathway genes will also be evaluated by qRT-PCR (3D). These results will contribute to a better understanding of the involvement of oxidative stress pathways in prostate cancer and reinforce the therapeutic potential of sulfiredoxin inhibition in the treatment of mCRPC.