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Two distinct antitumor patwways activated by transfected poly(I:C) in androgen-independent prostate cancer cells
No full textIntroduction
Prostate cancer (PCa) represents the second leading cause of cancer death in men and develops as a result of the accumulation of genetic and epigenetic alterations. Data from literature suggest that new therapeutic targets are emerging and in particular, it is known that the activation of Toll-like Receptors 3 (TLR3), expressed by cancer cells has a pro-apoptotic and thus anti-tumoral effect in different tumors (Cheng & Xu, 2010). We previously demonstrated that the synthetic analogue of dsRNA, poly(I:C), (specific TLR3-ligand), induces apoptosis in the androgen-dependent prostate cancer cell line LNCaP in a TLR3-dependent fashion, whereas a weaker apoptotic effect is observed in more aggressive and androgen-independent prostate cancer cell lines PC3 (Paone et al, 2008) and DU-145 (Galli et al, 2013). In this regard, we have recently demonstrated that the encapsulation of poly(I:C) with three different formulations of cationic liposomes were up to 10 times more efficient than the free drug in eliminating both PC3 and DU145 cells (Palchetti et al, 2013). These data suggest that transfected poly(I:C) could raise apoptotic rate by stimulating cytosolic dsRNA receptors. In the present paper we analyzed the receptors and signalling pathways involved in apoptosis induced by poly(I:C) transfected by lipofectamine (the most common transfection agent) compared with free poly(I:C) in PC3 and DU145 cells.
Material and Method
We evaluated cell viability by MTT assay and apoptosis by cell cycle analysis by FACS and caspase activity. SiRNA approach and Western Blot analysis were performed to determine the receptors and signal transduction molecules involved in transfected poly(I:C)-induced effects.
Results and discussion
Poly(I:C) transfected by lipofectamine [in-poly(I:C)] inhibits cell viability in PC3 and DU145 cells in a dose dependent manner with the highest efficiency at 2μg/ml of poly(I:C) compared to twelve-fold higher poly(I:C) concentration (25μg/ml) and induces caspase-dependent intrinsic and extrinsic apoptosis.
By using genetic inhibition of different poly(I:C) receptors we demonstrated the crucial role of TLR3 and Src in in-poly(I:C) induced apoptosis. Moreover, we show that IRF3-mediated signaling causes the upregulation of TLR3, cytosolic receptors (RLH) and interferon-beta expression. Our data highlight the multiple signaling triggered by in-poly(I:C) leading to antitumor responses.
Conclusion
We can conclude that the treatment of PC3 and DU145 cells with in-poly(I:C) activates two distinct anti-tumor pathways: one mediated by TLR3, dependent on Src leading to a remarkable apoptosis and the other one mediated by cytosolic receptors, dependent on IRF-3 leading to themselves up-regulation and interferon-beta expression
Necroptosis: Molecular Signalling and Translational Implications
Full text linkNecroptosis is a form of programmed necrosis whose molecular players are partially shared with apoptotic cell death. Here we summarize what is known about molecular signalling of necroptosis, particularly focusing on fine tuning of FLIP and IAP proteins in the apoptosis/necroptosis balance. We also emphasize necroptosis involvement in physiological and pathological conditions, particularly in the regulation of immune homeostasis
Transfected poly(I:C) activates different dsRNA receptors leading to apoptosis or immunoadjuvant response in androgen-independent prostate cancer cells
Full text linkBackground: Castration-resistant prostate cancer (CRPC) is refractory to chemo-radiotherapy.
Results: Transfection of the synthetic analog of dsRNA poly(I:C) simultaneously stimulates apoptosis and IFN- expression
through different pathways in androgen-independent prostate cancer (PCa) cells.
Conclusion: Dual parallel pathways triggered by distinct receptors activate direct and immunologically mediated antitumor
effects in advanced PCa.
Significance: The proapoptotic/immunoadjuvant poly(I:C)-Lipofectamine complex may offer new therapeutic insights into CRPC
TUMOR NECROSIS FACTOR-ALPHA INDUCES INTERLEUKIN-6 PRODUCTION AND INTEGRIN LIGAND EXPRESSION BY DISTINCT TRANSDUCTION PATHWAYS
No full textMolecular analysis of poly(I:C)-induced antitumor effects in androgen-independent prostate cancer cells
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HIF-1 activation by Toll Like Receptor-3 agonist poly (I:C) in prostate cancer cell line.
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