Naumann U, Bähr O, Wolburg H, Altenberend S, Wick W, Liston P, Ashkenazi A, Weller M
Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
Gene Ther. 2007 Jan;14(2):147-61. doi: 10.1038/sj.gt.3302845. Epub 2006 Sep 7.
The expression of inhibitor of apoptosis (IAP) family members contributes to the resistance of human cancers to apoptosis induced by radiotherapy and chemotherapy. We report that the infection of malignant glioma cells and several other tumor cell lines with adenoviruses encoding antisense RNA to X-linked IAP (XIAP) depletes endogenous XIAP levels and promotes global caspase activation and apoptosis. In contrast, non-neoplastic SV-FHAS human astrocytes and other non-neoplastic cells express XIAP at very low levels and resist these effects of adenovirus-expressing XIAP antisense RNA (Ad-XIAP-as). Caspase inhibitors such as z-Val-Ala-DL-Asp(OMe)-fluoromethylketone (zVAD-fmk) delay caspase processing and XIAP depletion, suggesting that XIAP depletion results both from antisense-mediated interference with protein synthesis and proteolytic cleavage by activated caspases. However, zVAD-fmk neither prevents nor delays cell death, indicating a caspase-independent pathway to cell death triggered by IAP depletion. Similarly, B-cell lymphoma-X(L) (BCL-X(L)) inhibits caspase activity, but fails to rescue from apoptosis. Loss of p65/nuclear factor-kappaB (NF-kappaB) protein and NF-kappaB activity is an early event triggered by Ad-XIAP-as and probably involved in Ad-XIAP-as-induced apoptosis. Finally, Ad-XIAP-as gene therapy induces cell death in intracranial glioma xenografts, prolongs survival in nude mice and may reduce tumorigenicity in synergy with Apo2L/TNF-related apoptosis-inducing ligand (TRAIL) in vivo. Altogether, these data define a powerful survival function for XIAP and reinforce its possible role as a therapeutic target in human glioma cells.
凋亡抑制蛋白（IAP）家族成员的表达促使人类癌症对放疗和化疗诱导的凋亡产生抗性。我们报告称，用编码X连锁凋亡抑制蛋白（XIAP）反义RNA的腺病毒感染恶性胶质瘤细胞和其他几种肿瘤细胞系，可降低内源性XIAP水平，并促进整体半胱天冬酶激活和凋亡。相比之下，非肿瘤性SV-FHAS人星形胶质细胞和其他非肿瘤细胞XIAP表达水平极低，对表达XIAP反义RNA的腺病毒（Ad-XIAP-as）的这些作用具有抗性。半胱天冬酶抑制剂如z-缬氨酰-丙氨酰-DL-天冬氨酸（甲酯）-氟甲基酮（zVAD-fmk）可延迟半胱天冬酶的加工和XIAP的消耗，这表明XIAP的消耗既是反义介导的对蛋白质合成的干扰所致，也是活化的半胱天冬酶进行蛋白水解切割的结果。然而，zVAD-fmk既不能预防也不能延迟细胞死亡，这表明IAP消耗引发的细胞死亡存在一条不依赖半胱天冬酶的途径。同样，B细胞淋巴瘤-XL（BCL-XL）抑制半胱天冬酶活性，但无法挽救细胞免于凋亡。p65/核因子-κB（NF-κB）蛋白和NF-κB活性的丧失是Ad-XIAP-as触发的早期事件，可能参与了Ad-XIAP-as诱导的凋亡。最后，Ad-XIAP-as基因疗法可诱导颅内胶质瘤异种移植物中的细胞死亡，延长裸鼠的生存期，并且在体内与Apo2L/肿瘤坏死因子相关凋亡诱导配体（TRAIL）协同作用时可能降低致瘤性。总之，这些数据确定了XIAP强大的生存功能，并强化了其作为人类胶质瘤细胞治疗靶点的潜在作用。
