Late phase activation of nuclear transcription factor kappaB by doxorubicin is mediated by interleukin-8 and induction of apoptosis via FasL (Retracted article. See vol. 138, pg. 977, 2013)
Late phase activation of nuclear transcription factor kappaB by doxorubicin is mediated by interleukin-8 and induction of apoptosis via FasL (Retracted article. See vol. 138, pg. 977, 2013)
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DOI：
10.1007/s10549-009-0493-z
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发表时间：
2010-04-01
影响因子：
3.8
通讯作者：
Manna, Sunil Kumar
中科院分区：
文献类型：
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作者：
Gangadharan, Charitha;Thoh, Maikho;Manna, Sunil Kumar
阿霉素是用于治疗各种肿瘤的最有效的分子之一。矛盾的报告往往打开窗口，了解阿霉素介导的信号发挥其凋亡作用。在这份报告中，我们提供的证据表明，阿霉素诱导双相诱导核因子κ B（NF-κ B）的立即激活，然后减少RelA（p65）亚基的数量可能是通过诱导蛋白酶体的活性，而不是蛋白酶。通过多柔比星处理表达的白细胞介素8（IL-8）观察到NF-κ B的进一步诱导。增加IL-8的量通过增加细胞内Ca 2+的释放、钙调磷酸酶的激活、核因子激活的T细胞（NF-AT）的核转位和NF-AT依赖的FasL表达来诱导细胞凋亡。抗IL-8或FasL抗体、显性负性TRAF 6（TRAF 6-DN）或TRAF 6结合肽（TRAF 6-BP）抑制阿霉素介导的NF-κ B的晚期诱导并减少细胞死亡。因此，我们的研究清楚地表明，阿霉素介导的细胞死亡是通过表达IL-8。IL-8介导的钙化是增强阿霉素介导的细胞死亡所必需的。总体而言，这项研究将有助于了解研究较多的化疗药物，阿霉素介导的细胞信号级联发挥其在化疗过程中的作用。
Doxorubicin is one of the most effective molecules used in the treatment of various tumors. Contradictory reports often open windows to understand the doxorubicin-mediated signaling to exert its apoptosis effect. In this report, we provide evidences that doxorubicin induced biphasic induction of nuclear factor kappaB (NF-kappa B) of immediate activation followed by decrease in the amount of RelA (p65) subunit possibly by inducing the activity of proteasome, but not proteases. Further induction of NF-kappa B was observed through interleukin 8 (IL-8), expressed by doxorubicin treatment. Increased amount of IL-8 induced apoptosis via increase in the releases of intracellular Ca2+, activation of calcineurin, nuclear translocation of nuclear factor activated T cell (NF-AT), and NF-AT-dependent FasL expression. Anti-IL-8 or -FasL antibody, dominant negative TRAF6 (TRAF6-DN), or TRAF6 binding peptide (TRAF6-BP) inhibited doxorubicin-mediated late phase induction of NF-kappa B and diminished cell death. Thus, our study clearly demonstrated that doxorubicin-mediated cell death is obtained through expression of IL-8. IL-8-mediated calcification is required for enhancement of doxorubicin-mediated cell death. Overall, this study will help to understand the much studied chemotherapeutic drug, doxorubicin-mediated cell signaling cascade to exert its effect during chemotherapy.