NF-κB activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells
NF-κB activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells
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DOI：
10.1074/jbc.m108674200
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发表时间：
2001-12-28
影响因子：
4.8
通讯作者：
Opipari, AW
中科院分区：
文献类型：
--
作者：
Bian, X;McAllister-Lucas, LM;Opipari, AW
神经母细胞瘤是儿童最常见的颅外实体瘤。N型神经母细胞瘤细胞（以SH-SY 5 Y和IMR 32细胞系为代表）的特征在于神经元表型。N型细胞系通常是N-myc扩增的，表达抗凋亡蛋白Bcl-2，不表达半胱天冬酶-8。本研究旨在确定N型细胞在通常用于治疗这种疾病的特定细胞毒性药物（如顺铂和阿霉素）的反应中死亡的机制。我们发现N型细胞对顺铂和阿霉素同样敏感。然而，顺铂诱导的死亡被非选择性半胱天冬酶抑制剂z-Val-Ala-Asp-fluoromethylketone或特异性半胱天冬酶-9抑制剂N-乙酰基-Leu-Glu-His-Asp-aldehyde抑制，而相比之下，半胱天冬酶抑制不能阻止阿霉素诱导的死亡。无论是活性氧还是线粒体通透性转换似乎在这个过程中发挥重要作用。多柔比星诱导NF-κ B转录激活与I-κ B α降解之前的细胞活力损失。令人惊讶的是，抗氧化剂和NF-κ B抑制剂吡咯烷二硫代氨基甲酸酯阻断了阿霉素诱导的NF-κ B转录激活，并提供了对阿霉素杀伤的深刻保护。此外，SH-SY 5 Y细胞表达的超阻遏形式的I-kappaB是完全耐阿霉素杀伤。总之，这些发现表明，NF-κ B活化介导阿霉素诱导的细胞死亡，没有证据表明半胱天冬酶功能，并表明顺铂和阿霉素参与不同的死亡途径杀死神经母细胞瘤细胞。
Neuroblastoma is the most common extracranial solid tumor of childhood. N-type neuroblastoma cells (represented by SH-SY5Y and IMR32 cell lines) are characterized by a neuronal phenotype. N-type cell lines are generally N-myc amplified, express the anti-apoptotic protein Bcl-2, and do not express caspase-8. The present study was designed to determine the mechanism by which N-type cells die in response to specific cytotoxic agents (such as cisplatin and doxorubicin) commonly used to treat this disease. We found that N-type cells were equally sensitive to cisplatin and doxorubicin. Yet death induced by cisplatin was inhibited by the nonselective caspase inhibitor z-Val-Ala-Asp-fluoromethylketone or the specific caspase-9 inhibitor N-acetyl-Leu-Glu-His-Asp-aldehyde, whereas in contrast, caspase inhibition did not prevent doxorubicin-induced death. Neither the reactive oxygen species nor the mitochondrial permeability transition appears to play an important role in this process. Doxorubicin induced NF-kappaB transcriptional activation in association with I-kappaBalpha degradation prior to loss of cell viability. Surprisingly, the antioxidant and NF-kappaB inhibitor pyrrolidine dithiocarbamate blocked doxorubicin-induced NF-kappaB transcriptional activation and provided profound protection against doxorubicin killing. Moreover, SH-SY5Y cells expressing a super-repressor form of I-kappaB were completely resistant to doxorubicin killing. Together these findings show that NF-kappaB activation mediates doxorubicin-induced cell death without evidence of caspase function and suggest that cisplatin and doxorubicin engage different death pathways to kill neuroblastoma cells.