Carcinogenesis Advance Access originally published online on June 19, 2008
Carcinogenesis 2008 29(7):1334-1342; doi:10.1093/carcin/bgn149
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Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-
-dependent mechanism
1 Department of Histology and Medical Embryology, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" University of Rome, 00161 Rome, Italy
2 Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy
* To whom correspondence should be addressed. Tel: +39 0649766582; Fax: +39 064462854; Email: anna.riccioli{at}uniroma1.it
Toll-like receptors (TLRs) are known to play a key role in the innate immune system particularly in inflammatory response against invading pathogens. Recent reports strongly indicate that they play important roles in cancer cells. Prostate cancer represents one of the most common cancer for which no cure is available once metastatic and androgen refractory. Since TLR3 has been recently suggested as a possible therapeutic target in some cancer cell lines, we studied TLR3 expression and functionality in two human prostate cancer cell lines, LNCaP and PC3. We report that both cell lines express TLR3 and that the TLR3 agonist poly (I:C) activates mitogen-activated protein kinases and induces inhibition of proliferation as well as caspase-dependent apoptosis. By using pharmacological and genetic approaches, we demonstrate the involvement of TLR3 in poly (I:C)-induced effects. We also show that a novel interferon-independent pathway involving protein kinase C (PKC)-
activation, upstream of p38 and c-jun N-terminal kinase, is responsible for poly (I:C) pro-apoptotic effects on LNCaP cells. To our knowledge, this is the first report describing a role of PKC- in poly (I:C)-mediated apoptosis. The comprehension of the mechanisms underlying TLR3-mediated apoptosis can contribute tools to develop new agonists useful for the treatment of prostate cancer.
Abbreviations: 7-AAD, 7-amino-actinomycin D; AR, androgen receptor; BrdU, 5-bromo-2-deoxyuridine; dsRNA, double-strand RNA; ERK, extracellular signal-regulated kinase; FCS, fetal calf serum; IFN, interferon; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; PBS, phosphate-buffered saline; PCa, prostate carcinoma; PI, propidium iodide; PKC-, protein kinase-; TIR, Toll/IL1R; TLR, Toll-like receptor; TUNEL, Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling; TLR3-DN, Toll-like receptor 3-dominant negative; WT, wild-type
Received February 20, 2008; revised May 28, 2008; accepted June 13, 2008.
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