Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer

Author(s)

Garcia, Patrick Vianna ^[1] ; Apolinario, Leticia Montanholi ^[1] ; Boeckelmann, Petra Karla ^[1] ; Nunes, Iseu da Silva ^[2] ; Duran, Nelson ^{[2, 3, 4]} ; Favaro, Wagner Jose ^{[1, 2]}

Affiliation

^[1] Univ Estadual Campinas, UNICAMP, Lab Urogenital Carcinogenesis & Immunotherapy, Dept Struct & Funct Biol, BR-13083865 Campinas, SP - Brazil

^[2] Farmabrasilis R&D Div, Campinas, SP - Brazil

^[3] Univ Estadual Campinas, UNICAMP, Biol Chem Lab, Inst Chem, BR-13083865 Campinas, SP - Brazil

^[4] Univ Estadual Campinas, UNICAMP, Inst Chem, NanoBioss, BR-13083865 Campinas, SP - Brazil

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY; v. 8, n. 5, p. 4427-4443, 2015.
• Web of Science Citations: 9

Abstract

The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERa and ER beta) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/or in combination with AR blockade may provide novel therapeutic approaches for NMIBC. (AU)

• FAPESP's process: 12/20706-2 - New therapeutic strategies for non-muscle invasive bladder cancer: effects of BCG and P-mapa immunotherapies on the steroid hormone receptors and reactive oxygen species
• Grantee: Wagner José Fávaro
• Support type: Regular Research Grants
• FAPESP's process: 12/13585-4 - EFFECTS OF INTRAVESICAL IMMUNOTHERAPIES WITH BCG AND P-MAPA ON SEXUAL STEROID HORMONES RECEPTORS AND REACTIVE OXYGEN SPECIES: POTENTIAL THERAPEUTIC STRATEGIES FOR URINARY BLADDER CANCER
• Grantee: Patrick Vianna Garcia
• Support type: Scholarships in Brazil - Post-Doctorate