Transfected Poly(I:C) Activates Different dsRNA Receptors, Leading to Apoptosis or Immunoadjuvant Response in Androgen-independent Prostate Cancer Cells

Despite the effectiveness of surgery or radiation therapy for the treatment of early-stage prostate cancer (PCa), there is currently no effective strategy for late-stage disease. New therapeutic targets are emerging; in particular, dsRNA receptors Toll-like receptor 3 (TLR3) and cytosolic helicases...

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Bibliographic Details
Published in:The Journal of biological chemistry 2015-02, Vol.290 (9), p.5470-5483
Main Authors: Palchetti, Sara, Starace, Donatella, De Cesaris, Paola, Filippini, Antonio, Ziparo, Elio, Riccioli, Anna
Format: Article
Language:English
Subjects:
Adjuvants, Immunologic - metabolism
Androgens - metabolism
Apoptosis - genetics
Blotting, Western
Cell Line, Tumor
DEAD-box RNA Helicases - genetics
DEAD-box RNA Helicases - metabolism
Double-stranded RNA (dsRNA)
Endosome
Gene Expression Regulation, Neoplastic
Humans
Innate Immunity
Interferon Regulatory Factor-3 - genetics
Interferon Regulatory Factor-3 - metabolism
Interferon-beta - genetics
Interferon-beta - metabolism
Interferon-Induced Helicase, IFIH1
Male
Microscopy, Confocal
Poly I-C - genetics
Poly I-C - metabolism
Prostate Cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Proto-Oncogene Proteins pp60(c-src) - genetics
Proto-Oncogene Proteins pp60(c-src) - metabolism
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA Interference
Signal Transduction
Signal Transduction - genetics
STAT1 Transcription Factor - genetics
STAT1 Transcription Factor - metabolism
Toll-like Receptor (TLR)
Toll-Like Receptor 3 - genetics
Toll-Like Receptor 3 - metabolism
Transfection
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary:Despite the effectiveness of surgery or radiation therapy for the treatment of early-stage prostate cancer (PCa), there is currently no effective strategy for late-stage disease. New therapeutic targets are emerging; in particular, dsRNA receptors Toll-like receptor 3 (TLR3) and cytosolic helicases expressed by cancer cells, once activated, exert a pro-apoptotic effect in different tumors. We previously demonstrated that the synthetic analog of dsRNA poly(I:C) induces apoptosis in the androgen-dependent PCa cell line LNCaP in a TLR3-dependent fashion, whereas only a weak apoptotic effect is observed in the more aggressive and androgen-independent PCa cells PC3 and DU145. In this paper, we characterize the receptors and the signaling pathways involved in the remarkable apoptosis induced by poly(I:C) transfected by Lipofectamine (in-poly(I:C)) compared with the 12-fold higher free poly(I:C) concentration in PC3 and DU145 cells. By using genetic inhibition of different poly(I:C) receptors, we demonstrate the crucial role of TLR3 and Src in in-poly(I:C)-induced apoptosis. Therefore, we show that the increased in-poly(I:C) apoptotic efficacy is due to a higher binding of endosomal TLR3. On the other hand, we show that in-poly(I:C) binding to cytosolic receptors MDA5 and RIG-I triggers IRF3-mediated signaling, leading uniquely to the up-regulation of IFN-β, which likely in turn induces increased TLR3, MDA5, and RIG-I proteins. In summary, in-poly(I:C) activates two distinct antitumor pathways in PC3 and DU145 cells: one mediated by the TLR3/Src/STAT1 axis, leading to apoptosis, and the other one mediated by MDA5/RIG-I/IRF3, leading to immunoadjuvant IFN-β expression. Castration-resistant prostate cancer (CRPC) is refractory to chemo-radiotherapy. Transfection of the synthetic analog of dsRNA poly(I:C) simultaneously stimulates apoptosis and IFN-β expression through different pathways in androgen-independent prostate cancer (PCa) cells. Dual parallel pathways triggered by distinct receptors activate direct and immunologically mediated antitumor effects in advanced PCa. The proapoptotic/immunoadjuvant poly(I:C)-Lipofectamine complex may offer new therapeutic insights into CRPC.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.601625