Transfected poly(I:C) activates different dsRNA receptors leading to apoptosis or immunoadjuvant response in androgen-independent prostate cancer cells [Cell Biology]

January 7th, 2015 by Palchetti, S., Starace, D., De Cesaris, P., Filippini, A., Ziparo, E., Riccioli, A.

Despite the effectiveness of surgery or radiation therapy for the treatment of early-stage of 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 analogue 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 more aggressive and androgen-independent PCa cells PC3 and DU145. In this paper we characterize the receptors and the signalling pathways involved in the remarkable apoptosis induced by poly(I:C) transfected by lipofectamine [in-poly(I:C)] compared to twelve-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 upregulation of IFN-β, that likely in turn induces increased TLR3, MDA5 and RIG-I proteins. To sum up, in-poly(I:C) activates two distinct anti-tumor 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.
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