TLR3 engagement induces IRF‐3‐dependent apoptosis in androgen‐sensitive prostate cancer cells and inhibits tumour growth in vivo

Journal of Cellular and Molecular Medicine

Guido Gambara²  Marianna Desideri⁴  Antonella Stoppacciaro³  Fabrizio Padula²  Paola De Cesaris¹  Donatella Starace²  Andrea Tubaro³  Donatella del Bufalo⁴  Antonio Filippini²  Elio Ziparo² 

[1] Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy;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;Department of Clinical and Experimental Medicine, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy;Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy

关键词: toll‐like receptor;    poly I:C;    IRF‐3;    apoptosis;    prostate cancer;   

DOI  :  10.1111/jcmm.12379

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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