Paone Alessio, Starace Donatella, Galli Roberta, Padula Fabrizio, De Cesaris Paola, Filippini Antonio, Ziparo Elio, Riccioli Anna
Department of Histology and Medical Embryology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy.
Carcinogenesis. 2008 Jul;29(7):1334-42. doi: 10.1093/carcin/bgn149. Epub 2008 Jun 19.
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.
Toll样受体（TLRs）在先天免疫系统中发挥关键作用，特别是在针对入侵病原体的炎症反应中。最近的报告有力地表明它们在癌细胞中也发挥着重要作用。前列腺癌是最常见的癌症之一，一旦发生转移且对雄激素耐药，就无法治愈。由于最近有研究表明TLR3可能是某些癌细胞系的治疗靶点，我们研究了TLR3在两种人前列腺癌细胞系LNCaP和PC3中的表达及功能。我们报告这两种细胞系均表达TLR3，并且TLR3激动剂聚肌苷酸-聚胞苷酸（poly (I:C)）可激活丝裂原活化蛋白激酶，并诱导细胞增殖抑制以及半胱天冬酶依赖性凋亡。通过药理学和遗传学方法，我们证明了TLR3参与了poly (I:C)诱导的效应。我们还表明，一种涉及蛋白激酶C（PKC）-α激活的新型非干扰素依赖性途径，在p38和c-jun氨基末端激酶的上游，是poly (I:C)对LNCaP细胞促凋亡作用的原因。据我们所知，这是第一份描述PKC-α在poly (I:C)介导的凋亡中作用的报告。对TLR3介导的凋亡潜在机制的理解可为开发用于治疗前列腺癌的新型激动剂提供帮助。
