Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism.
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)-alpha 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-alpha 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.
Department of Histology and Medical Embryology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy.
Alessio
A
Paone
Donatella
D
Starace
Roberta
R
Galli
Fabrizio
F
Padula
Paola
P
De Cesaris
Antonio
A
Filippini
Elio
E
Ziparo
Anna
A
Riccioli
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011070:Poly I-C / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D011944:Receptors, Androgen; C495901:TP53 protein, human; D051196:Toll-Like Receptor 3; D016159:Tumor Suppressor Protein p53; D016899:Interferon-beta; D051571:Protein Kinase C-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D011070:Poly I-C