Steinbach Joachim P, Wolburg Hartwig, Klumpp Andrea, Weller Michael
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, Medical School, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany.
J Neurochem. 2005 Mar;92(6):1340-9. doi: 10.1111/j.1471-4159.2004.02957.x.
Death ligands such as CD95 ligand (CD95L) have limited activity against glioma cells under normoxic conditions. Hypoxia is a critical aspect of the microenvironment of gliomas in vivo. We investigated the effect of co-exposure to acute hypoxia and CD95 ligand in three human malignant glioma cell lines with different susceptibility to CD95L under normoxic conditions. Hypoxia sensitized all three cell lines towards CD95L-induced cell death. Co-exposure resulted in apoptotic changes in the early phase, with gradual conversion to secondary necrosis with increasing length of hypoxia. The mitochondrial injury induced by hypoxia was enhanced by co-treatment, and caspase cleavage became prominent. Inhibition of the epidermal growth factor receptor (EGFR), although sensitizing glioma cells to CD95L under normoxia, protects glioma cells from hypoxia by reducing energy consumption. However, the opposing effects of EGFR signalling on death induced by CD95L or hypoxia were neutralized by co-exposure to hypoxia and CD95L. Furthermore, inhibition of protein synthesis by cycloheximide also reduced glucose consumption and conferred protection from hypoxia, but did not modulate CD95L-induced cell death under hypoxic conditions. These results suggest that death ligands may be useful to target hypoxic tumour cells resistant to conventional therapies or to complement strategies aiming at the induction of tumour hypoxia.
在常氧条件下，诸如CD95配体（CD95L）等死亡配体对胶质瘤细胞的活性有限。缺氧是体内胶质瘤微环境的一个关键方面。我们研究了在常氧条件下对三种对CD95L敏感性不同的人恶性胶质瘤细胞系同时暴露于急性缺氧和CD95配体的影响。缺氧使所有三种细胞系对CD95L诱导的细胞死亡敏感。同时暴露导致早期凋亡变化，随着缺氧时间延长逐渐转变为继发性坏死。缺氧诱导的线粒体损伤通过联合处理而增强，半胱天冬酶切割变得明显。表皮生长因子受体（EGFR）的抑制，虽然在常氧条件下使胶质瘤细胞对CD95L敏感，但通过减少能量消耗保护胶质瘤细胞免受缺氧影响。然而，EGFR信号传导对CD95L或缺氧诱导的死亡的相反作用通过同时暴露于缺氧和CD95L而被中和。此外，放线菌酮抑制蛋白质合成也减少了葡萄糖消耗并赋予对缺氧的保护作用，但在缺氧条件下不调节CD95L诱导的细胞死亡。这些结果表明，死亡配体可能有助于靶向对传统疗法耐药的缺氧肿瘤细胞或补充旨在诱导肿瘤缺氧的策略。
