title: 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.
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 (ERα and ERβ) 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.
authors.affiliation: Department of Structural and Functional Biology, Laboratory of Urogenital Carcinogenesis and Immunotherapy, University of Campinas (UNICAMP) Campinas, SP, Brazil.
authors.forename: Patrick Vianna
authors.initials: PV
authors.lastname: Garcia
authors.affiliation: Department of Structural and Functional Biology, Laboratory of Urogenital Carcinogenesis and Immunotherapy, University of Campinas (UNICAMP) Campinas, SP, Brazil.
authors.forename: Letícia Montanholi
authors.initials: LM
authors.lastname: Apolinário
authors.affiliation: Department of Structural and Functional Biology, Laboratory of Urogenital Carcinogenesis and Immunotherapy, University of Campinas (UNICAMP) Campinas, SP, Brazil.
authors.forename: Petra Karla
authors.initials: PK
authors.lastname: Böckelmann
authors.affiliation: Farmabrasilis R&D Division, Campinas, SP, Brazil, Biol Chem Lab., University of Campinas (UNICAMP) Campinas, SP, Brazil.
authors.forename: Iseu
authors.initials: I
authors.lastname: da Silva Nunes
authors.affiliation: Farmabrasilis R&D Division, Campinas, SP, Brazil, Biol Chem Lab., University of Campinas (UNICAMP) Campinas, SP, Brazil ; Institute of Chemistry, Biol Chem Lab., University of Campinas (UNICAMP) Campinas, SP, Brazil ; Institute of Chemistry, NanoBioss, University of Campinas (UNICAMP) Campinas, SP, Brazil.
authors.forename: Nelson
authors.initials: N
authors.lastname: Duran
authors.affiliation: Department of Structural and Functional Biology, Laboratory of Urogenital Carcinogenesis and Immunotherapy, University of Campinas (UNICAMP) Campinas, SP, Brazil ; Farmabrasilis R&D Division, Campinas, SP, Brazil, Biol Chem Lab., University of Campinas (UNICAMP) Campinas, SP, Brazil.
authors.forename: Wagner José
authors.initials: WJ
authors.lastname: Fávaro
mesh_terms: D000283:Administration, Intravesical; D000726:Androgen Antagonists / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D005485:Flutamide / Q000008:administration & dosage; D007167:Immunotherapy / Q000379:methods*; D008041:Linoleic Acids / Q000008:administration & dosage; D056918:Nuclear Receptor Coactivators / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage; D051381:Rats; D011916:Rats, Inbred F344; D011944:Receptors, Androgen / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
chemical_list: D000726:Androgen Antagonists; D008041:Linoleic Acids; C486560:Ncoa6 protein, rat; D056918:Nuclear Receptor Coactivators; D009943:Organophosphorus Compounds; D011944:Receptors, Androgen; C076534:magnesium ammonium phospholinoleate anhydride; D005485:Flutamide; D044767:Ubiquitin-Protein Ligases
keywords: Bladder cancer; N-CoR; P-MAPA; Siah2; androgen receptor; estrogen receptor; flutamide; immunotherapy; toll-like receptor