Helmholtz Center Munich–German Research Center for Environmental Health, Department of Gene Vectors, Marchioninistrasse 25, D-81377 Munich, Germany.
Clin Cancer Res. 2011 Dec 15;17(24):7605-13. doi: 10.1158/1078-0432.CCR-11-0513. Epub 2011 Oct 18.
Sensitivity of tumor cells toward chemotherapy mainly determines the prognosis of patients suffering from acute lymphoblastic leukemia (ALL); nevertheless, underlying mechanisms regulating chemosensitivity remain poorly understood. Here, we aimed at characterizing the role of caspase-8 for chemosensitivity of B- and T-ALL cells.
Primary tumor cells from children with ALL were evaluated for expression levels of the caspase-8 protein, were amplified in nonobese diabetic/severe combined immunodeficient mice, transfected with siRNA, and evaluated for their chemosensitivity in vitro.
Effective cell death in B- and T-ALL cells depended on the presence of caspase-8 for the majority of cytotoxic drugs routinely used in antileukemia treatment. Caspase-8 was activated independently from extrinsic apoptosis signaling. Accordingly in primary ALL cells, the expression level of caspase-8 protein correlated with cell death sensitivity toward defined cytotoxic drugs in vitro. In the subgroup of primary ALL cells, with low expression of caspase-8, methotrexate (MTX) upregulated the expression of caspase-8 mediated by the transcription factor p53, suggesting epigenetic silencing of caspase-8. RNA interference in patient-derived B- and T-ALL cells revealed that effective cell death induction by most routine drug combinations involving MTX depended on the presence of caspase-8.
Our results indicate that caspase-8 is crucial for the high antileukemic efficiency of numerous routine cytotoxic drugs. Reexpression of epigenetically downregulated caspase-8 represents a promising approach to increase efficiency of antileukemic therapy.
肿瘤细胞对化疗的敏感性主要决定了急性淋巴细胞白血病（ALL）患者的预后；然而，调节化疗敏感性的潜在机制仍知之甚少。在这里，我们旨在研究胱天蛋白酶-8（caspase-8）在 B 细胞和 T 细胞 ALL 细胞化疗敏感性中的作用。
评估来自 ALL 儿童的原代肿瘤细胞中 caspase-8 蛋白的表达水平，在非肥胖型糖尿病/重症联合免疫缺陷（NOD/SCID）小鼠中扩增，用 siRNA 转染，并在体外评估其化疗敏感性。
B 细胞和 T 细胞 ALL 细胞的有效细胞死亡取决于大多数用于白血病治疗的细胞毒药物中 caspase-8 的存在。Caspase-8 的激活独立于外在凋亡信号。因此，在原代 ALL 细胞中，caspase-8 蛋白的表达水平与体外对特定细胞毒药物的细胞死亡敏感性相关。在 caspase-8 低表达的原代 ALL 细胞亚组中，甲氨蝶呤（MTX）上调了由转录因子 p53 介导的 caspase-8 的表达，提示 caspase-8 的表观遗传沉默。在患者来源的 B 细胞和 T 细胞 ALL 细胞中的 RNA 干扰表明，大多数涉及 MTX 的常规药物组合诱导有效的细胞死亡依赖于 caspase-8 的存在。
我们的结果表明，caspase-8 对许多常规细胞毒药物的高效抗白血病作用至关重要。表观遗传下调的 caspase-8 的重新表达代表了提高抗白血病治疗效率的一种有前途的方法。
