title: TLR3 engagement induces IRF-3-dependent apoptosis in androgen-sensitive prostate cancer cells and inhibits tumour growth in vivo.
abstract: Toll-like receptors (TLRs) are a family of highly conserved transmembrane proteins expressed in epithelial and immune cells that recognize pathogen associated molecular patterns. Besides their role in immune response against infections, numerous studies have shown an important role of different TLRs in cancer, indicating these receptors as potential targets for cancer therapy. We previously demonstrated that the activation of TLR3 by the synthetic double-stranded RNA analogue poly I:C induces apoptosis of androgen-sensitive prostate cancer (PCa) LNCaP cells and, much less efficiently, of the more aggressive PC3 cell line. Therefore, in this study we selected LNCaP cells to investigate the mechanism of TLR3-mediated apoptosis and the in vivo efficacy of poly I:C-based therapy. We show that interferon regulatory factor-3 (IRF-3) signalling plays an essential role in TLR3-mediated apoptosis in LNCaP cells through the activation of the intrinsic and extrinsic apoptotic pathways. Interestingly, hardly any apoptosis was induced by poly I:C in normal prostate epithelial cells RWPE-1. We also demonstrate for the first time the direct anticancer effect of poly I:C as a single therapeutic agent in a well-established human androgen-sensitive PCa xenograft model, by showing that tumour growth is highly impaired in poly I:C-treated immunodeficient mice. Immunohistochemical analysis of PCa xenografts highlights the antitumour role of poly I:C in vivo both on cancer cells and, indirectly, on endothelial cells. Notably, we show the presence of TLR3 and IRF-3 in both human normal and PCa clinical samples, potentially envisaging poly I:C-based therapy for PCa.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Gambara
authors.forename: Marianna
authors.initials: M
authors.lastname: Desideri
authors.forename: Antonella
authors.initials: A
authors.lastname: Stoppacciaro
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Padula
authors.forename: Paola
authors.initials: P
authors.lastname: De Cesaris
authors.forename: Donatella
authors.initials: D
authors.lastname: Starace
authors.forename: Andrea
authors.initials: A
authors.lastname: Tubaro
authors.forename: Donatella
authors.initials: D
authors.lastname: Del Bufalo
authors.forename: Antonio
authors.initials: A
authors.lastname: Filippini
authors.forename: Elio
authors.initials: E
authors.lastname: Ziparo
authors.forename: Anna
authors.initials: A
authors.lastname: Riccioli
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000728:Androgens; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3
keywords: IRF-3; apoptosis; poly I:C; prostate cancer; toll-like receptor