Weiler M, Bähr O, Hohlweg U, Naumann U, Rieger J, Huang H, Tabatabai G, Krell H W, Ohgaki H, Weller M, Wick W
Laboratory of Molecular Neuro-Oncology, Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, Tübingen D-72076, Germany.
Cell Death Differ. 2006 Jul;13(7):1156-69. doi: 10.1038/sj.cdd.4401786. Epub 2005 Oct 28.
Conditionally BCL-xL-overexpressing LNT-229 Tet-On glioma cell clones were generated to investigate whether the 'antiapoptosis phenotype' and the 'motility phenotype' mediated by BCL-2 family proteins in glioma cells could be separated. BCL-xL induction led to an immediate and concentration-dependent protection of LNT-229 cells from apoptosis. BCL-xL induction for up to 3 days did not result in altered invasiveness. In contrast, long-term BCL-xL induction for 21 days resulted in increased transforming growth factor-beta2 expression, and in metalloproteinase-2 and -14 dependent, but integrin independent, increased invasiveness. Withdrawal of doxycycline (Dox) abolished the protection from apoptosis whereas the 'invasion phenotype' remained stable. Dox stimulation of BCL-xL-inducible LNT-229 cells conferred infiltrative growth to BCL-xL-positive glioma cells in vivo and reduced the survival of tumor-bearing mice. These data allow to dissect a direct antiapoptotic action of BCL-xL from an indirect effect, presumably mediated by altered gene expression, which modifies tumor cell invasiveness in vitro and in vivo.
为了研究胶质瘤细胞中由BCL-2家族蛋白介导的“抗凋亡表型”和“运动表型”是否可以分离，构建了条件性过表达BCL-xL的LNT-229 Tet-On胶质瘤细胞克隆。BCL-xL的诱导导致LNT-229细胞立即受到浓度依赖性的抗凋亡保护。诱导BCL-xL达3天不会导致侵袭性改变。相反，长期诱导BCL-xL 21天会导致转化生长因子-β2表达增加，并导致金属蛋白酶-2和-14依赖性但整合素非依赖性的侵袭性增加。撤除强力霉素（Dox）可消除抗凋亡保护作用，而“侵袭表型”保持稳定。对BCL-xL可诱导的LNT-229细胞进行Dox刺激，可使BCL-xL阳性胶质瘤细胞在体内呈浸润性生长，并降低荷瘤小鼠的存活率。这些数据有助于从间接作用（可能由基因表达改变介导，这种改变会在体外和体内改变肿瘤细胞的侵袭性）中剖析BCL-xL的直接抗凋亡作用。
