Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism.
Paone, Alessio ; Starace, Donatella ; Galli, Roberta ; et al. ; - ASI Sponsor
Jul - 2008
ISSN : 1460-2180 ;
journal : Carcinogenesis

Issue : 7
type: Article Journal

Abstract
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.

keywords : Androgen,Androgen: biosynthesis,Androgen: genetics,Apoptosis,Apoptosis: drug effects,Apoptosis: physiology,Cell Growth Processes,Cell Growth Processes: drug effects,Cell Growth Processes: physiology,Cell Line,Enzyme Activation,Humans,Interferon-beta,Interferon-beta: metabolism,MAP Kinase Kinase 4,MAP Kinase Kinase 4: metabolism,Male,Mitogen-Activated Protein Kinases,Mitogen-Activated Protein Kinases: antagonists \& i,Mitogen-Activated Protein Kinases: metabolism,Phosphorylation,Poly I-C,Poly I-C: pharmacology,Prostatic Neoplasms,Prostatic Neoplasms: enzymology,Prostatic Neoplasms: genetics,Prostatic Neoplasms: metabolism,Prostatic Neoplasms: pathology,Protein Kinase C-alpha,Protein Kinase C-alpha: metabolism,Receptors,Toll-Like Receptor 3,Toll-Like Receptor 3: antagonists \& inhibitors,Toll-Like Receptor 3: metabolism,Transfection,Tumor,Tumor Suppressor Protein p53,Tumor Suppressor Protein p53: biosynthesis,Tumor Suppressor Protein p53: genetics,p38 Mitogen-Activated Protein Kinases,p38 Mitogen-Activated Protein Kinases: metabolism