Luciano F, Ricci J E, Herrant M, Bertolotto C, Mari B, Cousin J L, Auberger P
INSERM U 526, Activation des cellules Hématopoïétiques, Equipe labellisée par la Ligue Nationale contre le Cancer, IFR 50, Faculté de Médecine, Nice, France.
Leukemia. 2002 Apr;16(4):700-7. doi: 10.1038/sj.leu.2402401.
The execution phase of apoptosis occurs through the activation and function of caspases which cleave key substrates that orchestrate the death process. Here, we have compared the sensitivity of various T and B cell lines to death receptor or staurosporine-induced apoptosis. First, we found a lack of correlation between death receptor expression and sensitivity to Fas or Trail. By contrast, a correlation between caspase activation, DNA fragmentation and cell death in T cell lines was evidenced. Among T cells, CEM underwent apoptosis in response to CH11 but were resistant to Trail in agreement with the absence of Trail receptors (DR4 and DR5) on their surface. The B cell line SKW 6.4 was sensitive to CH11 and staurosporine but resistant to Trail. As B cell lines expressed significant levels of DR4 and DR5, resistance to Trail in SKW 6.4 is likely due to the expression of the decoy receptor DcR1. Burkitt's lymphoma such as RPMI 8866 and Raji did not exhibit DNA fragmentation in response to CH11, Trail or staurosporine but showed long-term caspase-dependent loss of viability upon effector treatment. The B cell lines used in this study express very weak or undetectable levels of DFF40 and relatively high levels of DFF45. Interestingly, cytosolic extracts from RPMI 88.66 but not other B lymphoma exhibit altered levels of cytochrome c-dependent caspase activation. Taken together, our results show that: (1) death receptor expression does not correlate with sensitivity to apoptosis; (2) the very low ratio of DFF40 vs. DFF45 is unlikely to explain by itself the lack of DNA fragmentation observed in certain B cell lines; and (3) a defective cytochrome c-dependent caspase activation might account at least in part for the insensitivity of certain Burkitt's lymphoma (RPMI 88.66) to apoptosis. Thus it seems that resistance of Burkitt's lymphoma to apoptosis is not governed by a general mechanism, but is rather multifactorial and differs from one cell line to another.
凋亡的执行阶段通过半胱天冬酶的激活和功能来实现，这些酶会切割协调死亡过程的关键底物。在此，我们比较了各种T细胞和B细胞系对死亡受体或星形孢菌素诱导的凋亡的敏感性。首先，我们发现死亡受体表达与对Fas或肿瘤坏死因子相关凋亡诱导配体（TRAIL）的敏感性之间缺乏相关性。相比之下，在T细胞系中证实了半胱天冬酶激活、DNA片段化与细胞死亡之间存在相关性。在T细胞中，CEM细胞对CH11有反应而发生凋亡，但对TRAIL有抗性，这与其表面缺乏TRAIL受体（DR4和DR5）一致。B细胞系SKW 6.4对CH11和星形孢菌素敏感，但对TRAIL有抗性。由于B细胞系表达显著水平的DR4和DR5，SKW 6.4对TRAIL的抗性可能是由于诱饵受体DcR1的表达。伯基特淋巴瘤如RPMI 8866和Raji细胞对CH11、TRAIL或星形孢菌素无反应而未出现DNA片段化，但在效应细胞处理后显示出长期的半胱天冬酶依赖性活力丧失。本研究中使用的B细胞系表达非常低或无法检测到的DNA片段化因子40（DFF40）水平以及相对较高的DNA片段化因子45（DFF45）水平。有趣的是，RPMI 88.66细胞的胞质提取物而非其他B淋巴瘤细胞的提取物显示出细胞色素c依赖性半胱天冬酶激活水平的改变。综上所述，我们的结果表明：（1）死亡受体表达与凋亡敏感性不相关；（2）DFF40与DFF45的极低比例本身不太可能解释某些B细胞系中观察到的DNA片段化缺乏现象；（3）细胞色素c依赖性半胱天冬酶激活缺陷可能至少部分解释了某些伯基特淋巴瘤（RPMI 88.
