E. Ziparo - The role of Toll Like Receptors in immune responses to infections and in inflammation associated pathologies cer risk provides evidence for a role of TLRs in prostate cancer. Moreover, conflicting <strong>report</strong>s have been published claiming pro- or anti-tumoral effects of TLR9 agonist on human prostate cancer cell lines. Mounting evidence shows that the enhancement of innate and adaptive immunity represents the principal mechanism by which TLR stimulation produces antitumour activity. However, a direct pro-apoptotic effect of TLR agonists on TLR3 + and TLR9 + tumour cells has been recently <strong>report</strong>ed (Salaun, J Immunol. 2006; Salaun, Clin. Cancer Res. 2007). Based on this evidence, in order to elucidate the role of TLRs in the etiology and pathogenesis of prostate cancer, we used as experimental model three different cell lines: the prostatic benign human hyperplasia cell line BPH-1, the androgen responsive cell line LNCaP and the androgen unresponsive PC3 cell line. Firstly, we investigated the effect of the TLR3 agonist poly (I:C) on the proliferative and apoptotic rates of LNCaP and PC3. We demonstrated that poly (I:C) elicits inhibition of proliferation associated with a significant induction of TLR3-mediated apoptosis in both prostate cancer cell lines. However, we found that LNCaP cells are very sensitive to poly (I:C)induced apoptosis, whereas PC3 cells, a more aggressive prostate cancer cell line, shows a significant resistance to this apoptotic stimulus. Among differently expressed genes in two cell lines, WT p53 and androgen receptor (AR) are expressed in LNCaP cells, whereas PC3 cells, , are null for both p53 and AR. The dependence of prostate tumour on AR activity is exploited in treatment of disseminated prostate cancers, wherein ablation of AR function induces the regression of prostate tumours mainly through increased apoptosis. Tumour progression is associated with inappropriately restored AR function, despite sustained androgen ablation and/or the 110 use of AR antagonists (Hsieh, Lancet Oncol. 2007) Since PC3 cells lack AR and p53 expression, the differences in response to poly (I:C) between LNCaP and PC3 cells might result from variations in the AR and p53 status of these cells. To determine whether these differences may account for the minor susceptibility of PC3 cells to poly (I:C)-induced effects, we performed apoptosis assay on PC3 cells stably transfected with AR plasmid or transiently transfected with p53 plasmid (PC3–p53) and treated with poly (I:C). Our results indicate that forced expression of AR in androgen-independent prostate cancer cell lines confers a higher sensitivity to poly (I:C)induced apoptosis, whereas no increment of apoptosis was observed in PC3–p53 cells. Finally, we identified a new IFN-B-independent pathway that involves protein kinase C (PKC)-alpha activation as responsible for the poly (I:C)-mediated apoptosis in LNCaP cell line. Selected publications Dal Secco V, Riccioli A, Padula F, Ziparo E, Filippini A. Mouse Sertoli cells display phenotypical and functional traits of antigen-presenting cells in response to interferon gamma. Biol Reprod. 2008, 78: 234-42. Paone A, Starace D, Galli R, Padula F, De Cesaris P, Filippini A, Ziparo E, Riccioli A. Toll like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanisms. Carcinogenesis 2008, 29:1334-42. Starace D, Galli R, Paone A, De Cesaris P, Filippini A, Ziparo E, Riccioli A. Toll-like receptor 3 activation induces antiviral immune responses in mouse Sertoli cells. Biol Reprod. 2008, 79: 766-75.
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