Open AccessTLR 3 engagement induces IRF ‐3‐dependent apoptosis in androgen‐sensitive prostate cancer cells and inhibits tumour growth in vivo
Author(s) -
Gambara Guido,
Desideri Marianna,
Stoppacciaro Antonella,
Padula Fabrizio,
De Cesaris Paola,
Starace Donatella,
Tubaro Andrea,
Bufalo Donatella,
Filippini Antonio,
Ziparo Elio,
Riccioli Anna
Publication year - 2015
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12379
Subject(s) - lncap , prostate cancer , cancer research , androgen receptor , apoptosis , biology , tlr3 , cancer cell , in vivo , innate immune system , microbiology and biotechnology , immune system , cancer , toll like receptor , immunology , biochemistry , genetics
Toll‐like receptors ( TLR s) 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 TLR s in cancer, indicating these receptors as potential targets for cancer therapy. We previously demonstrated that the activation of TLR 3 by the synthetic double‐stranded RNA analogue poly I:C induces apoptosis of androgen‐sensitive prostate cancer ( PC a) LNC aP cells and, much less efficiently, of the more aggressive PC 3 cell line. Therefore, in this study we selected LNC aP cells to investigate the mechanism of TLR 3‐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 TLR 3‐mediated apoptosis in LNC aP 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 PC a xenograft model, by showing that tumour growth is highly impaired in poly I:C‐treated immunodeficient mice. Immunohistochemical analysis of PC a 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 TLR 3 and IRF ‐3 in both human normal and PC a clinical samples, potentially envisaging poly I:C‐based therapy for PC a.