Colombatti Marco, Grasso Silvia, Porzia Alessandra, Fracasso Giulio, Scupoli Maria Teresa, Cingarlini Sara, Poffe Ornella, Naim Hassan Y, Heine Martin, Tridente Giuseppe, Mainiero Fabrizio, Ramarli Dunia
Department of Pathology, University of Verona, Verona, Italy.
PLoS One. 2009;4(2):e4608. doi: 10.1371/journal.pone.0004608. Epub 2009 Feb 26.
The interleukin-6 (IL-6) and the chemokine CCL5 are implicated in the development and progression of several forms of tumours including that of the prostate. The expression of the prostate specific membrane antigen (PSMA) is augmented in high-grade and metastatic tumors. Observations of the clinical behaviour of prostate tumors suggest that the increased secretion of IL-6 and CCL5 and the higher expression of PSMA may be correlated. We hypothesized that PSMA could be endowed with signalling properties and that its stimulation might impact on the regulation of the gene expression of IL-6 and CCL5. We herein demonstrate that the cross-linking of cell surface PSMA with specific antibodies activates the small GTPases RAS and RAC1 and the MAPKs p38 and ERK1/2 in prostate carcinoma LNCaP cells. As downstream effects of the PSMA-fostered RAS-RAC1-MAPK pathway activation we observed a strong induction of NF-kappaB activation associated with an increased expression of IL-6 and CCL5 genes. Pharmacological blockade with specific inhibitors revealed that both p38 and ERK1/2 participate in the phenomenon, although a major role exerted by p38 was evident. Finally we demonstrate that IL-6 and CCL5 enhanced the proliferative potential of LNCaP cells synergistically and in a dose-dependent manner and that CCL5 functioned by receptor-mediated activation of the STAT5-Cyclin D1 pro-proliferative pathway. The novel functions attributable to PSMA which are described in the present report may have profound influence on the survival and proliferation of prostate tumor cells, accounting for the observation that PSMA overexpression in prostate cancer patients is related to a worse prognosis.
白细胞介素-6（IL-6）和趋化因子CCL5与包括前列腺癌在内的多种肿瘤的发生和发展有关。前列腺特异性膜抗原（PSMA）在高级别和转移性肿瘤中的表达增加。对前列腺肿瘤临床行为的观察表明，IL-6和CCL5分泌增加与PSMA表达升高可能相关。我们推测PSMA可能具有信号传导特性，其刺激可能会影响IL-6和CCL5基因表达的调控。我们在此证明，用特异性抗体交联细胞表面PSMA可激活前列腺癌LNCaP细胞中的小GTP酶RAS和RAC1以及丝裂原活化蛋白激酶p38和ERK1/2。作为PSMA促进的RAS-RAC1-MAPK途径激活的下游效应，我们观察到NF-κB激活的强烈诱导，同时伴有IL-6和CCL5基因表达增加。用特异性抑制剂进行药理阻断显示，p38和ERK1/2均参与了这一现象，尽管p38发挥了主要作用。最后，我们证明IL-6和CCL5协同且以剂量依赖的方式增强了LNCaP细胞的增殖潜力，并且CCL5通过受体介导的STAT5-细胞周期蛋白D1促增殖途径发挥作用。本报告中描述的PSMA的新功能可能对前列腺肿瘤细胞的存活和增殖产生深远影响，这解释了前列腺癌患者中PSMA过表达与预后较差相关的观察结果。
