Rieger J, Naumann U, Glaser T, Ashkenazi A, Weller M
Department of Neurology, University of Tübingen, School of Medicine, Germany.
FEBS Lett. 1998 May 1;427(1):124-8. doi: 10.1016/s0014-5793(98)00409-8.
APO2L (TRAIL) is a novel CD95L (Fas/APO-1-L) homologous cytotoxic cytokine that interacts with various receptors which transmit (DR4, DR5) or inhibit (DcR1, DcR2) an apoptotic signal. Here, we report that human glioma cell lines preferentially express mRNAs for agonistic death receptors DR4 (8/12) and DR5 (11/12) rather than the death-inhibitory decoy receptors DcR1 (4/12) and DcR2 (2/12). Ten of 12 cell lines are susceptible to APO2L-induced apoptosis. The resistant cell lines, U138MG and U373MG, are cross-resistant to CD95L-induced apoptosis. Similar to CD95L-induced apoptosis, APO2L-induced apoptosis is inhibited by ectopic expression of the caspase inhibitor, crm-A, or of bcl-2, or by coexposure to the corticosteroid, dexamethasone, or the lipoxygenase inhibitor, nordihydroguaretic acid. There is no correlation between p53 genetic status of the cell lines and their susceptibility to APO2L-induced apoptosis, but the latter is moderately enhanced by ectopic expression of wild-type p53. APO2L targeting may be a promising approach for selectively targeting apoptosis to human malignant glioma cells.
APO2L（肿瘤坏死因子相关凋亡诱导配体）是一种新型的与CD95L（Fas/APO-1-L）同源的细胞毒性细胞因子，它可与多种能传递（DR4、DR5）或抑制（DcR1、DcR2）凋亡信号的受体相互作用。在此，我们报告人类胶质瘤细胞系优先表达促凋亡死亡受体DR4（12个中有8个）和DR5（12个中有11个）的mRNA，而非死亡抑制性诱饵受体DcR1（12个中有4个）和DcR2（12个中有2个）。12个细胞系中有10个对APO2L诱导的凋亡敏感。耐药细胞系U138MG和U373MG对CD95L诱导的凋亡具有交叉耐药性。与CD95L诱导的凋亡相似，APO2L诱导的凋亡可被胱天蛋白酶抑制剂crm-A或bcl-2的异位表达所抑制，或被同时暴露于皮质类固醇地塞米松或脂氧合酶抑制剂去甲二氢愈创木酸所抑制。细胞系的p53基因状态与其对APO2L诱导凋亡的敏感性之间无相关性，但野生型p53的异位表达可适度增强后者。靶向APO2L可能是一种有前景的方法，可选择性地使人类恶性胶质瘤细胞发生凋亡。
