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Carcinogenesis Advance Access published online on June 19, 2008
Carcinogenesis, doi:10.1093/carcin/bgn149
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

TOLL-LIKE RECEPTOR 3 TRIGGERS APOPTOSIS OF HUMAN PROSTATE CANCER CELLS THROUGH A PKC-{alpha} DEPENDENT MECHANISM

Alessio Paone1, Donatella Starace1, Roberta Galli1, Fabrizio Padula1, Paola De Cesaris2, Antonio Filippini1, Elio Ziparo1 and Anna Riccioli1

1 Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Histology and Medical Embryology, "Sapienza" University of Rome, 00161 Rome, Italy
2 Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy

Corresponding author: Anna Riccioli, Department of Histology and Medical Embryology, "Sapienza" University of Rome, 00161 Rome, Italy. Phone: +390649766582, Fax: +39064462854. E-mail: 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 MAPKs 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 IFN-independent pathway involving PKC- {alpha} activation, upstream of p38 and JNK, 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.

Key Words: Toll-like receptor • prostate cancer • apoptosis • MAPK • cell signalling

Received February 20, 2008; revised May 28, 2008; accepted June 13, 2008.


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