Taieb David, Roignot Julie, André Frédéric, Garcia Stéphane, Masson Bénédicte, Pierres Anne, Iovanna Juan-Lucio, Soubeyran Philippe
INSERM U.624, Marseille cedex 9, France.
Cancer Res. 2008 Jun 15;68(12):4588-96. doi: 10.1158/0008-5472.CAN-08-0958.
The poor prognosis of pancreatic cancer is due to rapid locoregional invasion, the early development of metastases, and the limited efficacy of current therapies. To date, none of the identified oncogenes and suppressors involved in this disease have led to efficient treatments. Here, we describe that the scaffold protein ArgBP2 is repressed during oncogenic transformation of the pancreas. We could show, using a pancreatic cancer cell line model, that this repression of ArgBP2 participates in the progression of this disease. Interestingly, in vitro analyses revealed that the antitumoral potential of ArgBP2 is linked to the control of cell adhesion and migration rather than to the regulation of cell proliferation or sensitivity to apoptosis. Moreover, we could detail part of the molecular mechanism responsible by identifying new ArgBP2-interacting proteins, and show that this function is partly achieved by the control of a WAVE/PTP-PEST/c-Abl signaling complex. These findings point to a new mechanism of pancreatic cancer progression leading to invasion and metastasis and suggest that the ArgBP2 signaling pathway could represent a new target for cancer therapy.
胰腺癌预后较差，原因在于其局部区域侵袭迅速、转移出现早以及当前治疗方法疗效有限。迄今为止，已确定的参与该疾病的癌基因和抑癌基因均未带来有效的治疗方法。在此，我们描述了支架蛋白ArgBP2在胰腺致癌转化过程中受到抑制。利用胰腺癌细胞系模型，我们能够证明ArgBP2的这种抑制作用参与了该疾病的进展。有趣的是，体外分析表明，ArgBP2的抗肿瘤潜力与细胞黏附和迁移的控制有关，而非与细胞增殖调控或对凋亡的敏感性有关。此外，通过鉴定新的与ArgBP2相互作用的蛋白质，我们能够详细阐述部分分子机制，并表明该功能部分是通过对WAVE/PTP - PEST/c - Abl信号复合物的控制来实现的。这些发现指出了一种导致侵袭和转移的胰腺癌进展新机制，并表明ArgBP2信号通路可能代表癌症治疗的一个新靶点。
