Gdynia Georg, Grund Kerstin, Eckert Anika, Böck Barbara C, Funke Benjamin, Macher-Goeppinger Stephan, Sieber Sebastian, Herold-Mende Christel, Wiestler Benedict, Wiestler Otmar D, Roth Wilfried
Molecular Neuro-Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Mol Cancer Res. 2007 Dec;5(12):1232-40. doi: 10.1158/1541-7786.MCR-07-0343.
Glioblastomas, the most malignant of all brain tumors, are characterized by cellular resistance to apoptosis and a highly invasive growth pattern. These factors contribute to the poor response of glioblastomas to radiochemotherapy and prevent their complete neurosurgical resection. However, the driving force behind the distinct motility of glioma cells is only partly understood. Here, we report that in the absence of cellular stress and proapoptotic stimuli, human glioblastoma cells exhibit a constitutive activation of caspases in vivo and in vitro. The inhibition of caspases by various peptide inhibitors decreases the migration of cells in scrape motility assays and the invasiveness of cells in spheroid assays. Similarly, specific small interfering RNA- or antisense-mediated down-regulation of caspase-3 and caspase-8 results in an inhibition of the migratory potential of glioma cells. The constitutive caspase-dependent motility of glioblastoma cells is independent of CD95 activation and it is not mediated by mitogen-activated protein/extracellular signal-regulated kinase kinase signaling. The basal caspase activity is accompanied by a constant cleavage of the motility-associated gelsolin protein, which may contribute to the caspase-mediated promotion of migration and invasiveness in glioblastoma cells. Our results suggest that the administration of low doses of caspase inhibitors that block glioma cell motility without affecting the execution of apoptotic cell death may be exploited as a novel strategy for the treatment of glioblastomas.
胶质母细胞瘤是所有脑肿瘤中恶性程度最高的，其特征是细胞对凋亡具有抗性以及具有高度侵袭性的生长模式。这些因素导致胶质母细胞瘤对放化疗反应不佳，并阻碍其进行完整的神经外科切除。然而，胶质瘤细胞独特运动性背后的驱动力仅得到部分理解。在此，我们报告在不存在细胞应激和促凋亡刺激的情况下，人胶质母细胞瘤细胞在体内和体外均表现出半胱天冬酶的组成性激活。各种肽抑制剂对半胱天冬酶的抑制作用降低了划痕运动试验中细胞的迁移以及球体试验中细胞的侵袭性。同样，特异性小干扰RNA或反义介导的半胱天冬酶-3和半胱天冬酶-8下调导致胶质瘤细胞迁移潜能的抑制。胶质母细胞瘤细胞组成性的依赖半胱天冬酶的运动性独立于CD95激活，且不由丝裂原活化蛋白/细胞外信号调节激酶激酶信号传导介导。基础半胱天冬酶活性伴随着与运动相关的凝溶胶蛋白的持续切割，这可能有助于半胱天冬酶介导的胶质母细胞瘤细胞迁移和侵袭促进作用。我们的结果表明，给予低剂量的半胱天冬酶抑制剂来阻断胶质瘤细胞运动性而不影响凋亡性细胞死亡的执行，可能被开发为一种治疗胶质母细胞瘤的新策略。
