Camptothecin Fails to Induce Apoptosis in Tumor Necrosis Factor-Alpha-Treated HaCaT Cells
Camptothecin Fails to Induce Apoptosis in Tumor Necrosis Factor-Alpha-Treated HaCaT Cells
复制标题
喜树碱未能诱导肿瘤坏死因子 α 处理的 HaCaT 细胞凋亡
DOI：
10.1159/000335370
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发表时间：
2012-01-01
期刊：
影响因子：
3.1
通讯作者：
Hu, Jinhong
中科院分区：
文献类型：
--
作者：
Sun, Jun;Han, Jinzhao;Hu, Jinhong
喜树碱（Camptothecin，CPT）是一种DNA拓扑异构酶I抑制剂，最初从中国喜树（Camptotheca acuminata）果实中分离得到。CPT及其衍生物在中国已用于治疗银屑病和癌症数十年。众所周知，肿瘤坏死因子-α（TNF-α）是银屑病发病机制中的关键促炎细胞因子。在这项研究中，我们研究了CPT对TNF-α处理的HaCaT细胞的影响。结果表明，浓度范围为0.5-2.0 μ g/ml的CPT在HaCaT细胞中没有显示任何促凋亡作用。g.ml发现CPT和TNF-α均上调HaCaT细胞中TRAIL受体1/2的表达，但不上调TRAIL的表达。此外，抗凋亡蛋白（IAP 1，IAP 2和BcI-X-L）的表达上调TNF-α和抑制CPT在HaCaT细胞。因为这些基因产物已知受核因子-κ B（NF-κ B）调节，我们研究了CPT对NF-κ B活化的作用。发现CPT不仅不能抑制TNF-α诱导的NF-κ B活化，而且还促进NF-κ B活化。除了这些作用外，CPT还促进HaCaT细胞中类似于TNF-α的白细胞介素-6的产生。总之，尽管有充分的证据支持CPT诱导的癌细胞凋亡，我们的研究清楚地表明，CPT未能显示任何促凋亡作用的HaCaT细胞，即使它增强TRAIL受体1/2的表达和抑制TNF-α诱导的抗凋亡蛋白的表达。总之，这项研究表明，CPT未能阻断TNF-α的活性。关于CPT的NE-κ B激活作用，我们建议应重新评估CPT治疗银屑病的益处。版权所有（C）20125. Karger AG，巴塞尔
Camptothecin (CPT), a DNA topoisomerase I inhibitor, was originally isolated from the fruits of the Chinese Camptotheca acuminata tree. CPT and its derivatives have been used in the treatment of psoriasis and cancer in China for decades. It is well known that tumor necrosis factor-alpha (TNF-alpha) is a key proinflammatory cytokine in the pathogenesis of psoriasis. In this study, we investigated the effect of CPT on TNF-alpha-treated HaCaT cells. The results indicated that CPT in the concentration range of 0.5-2.0 mu g.ml(-1) failed to show any proapoptotic effect in HaCaT cells. It was found that both CPT and TNF-alpha up-regulated the expression of TRAIL receptor 1/2 but not TRAIL in HaCaT cells. Furthermore, the expression of antiapoptotic proteins (IAP1, IAP2, and BcI-X-L) was up-regulated by TNF-alpha and suppressed by CPT in HaCaT cells. Because these gene products are known to be regulated by nuclear factor-kappa B (NF-kappa B), we examined the role of CPT on NF-kappa B activation. It was found that CPT not only failed to inhibit TNF-alpha-induced NF-kappa B activation but also contributed to NF-kappa B activation. In addition to these effects, CPT also promoted the production of interleukin-6, similar to TNF-alpha, in HaCaT cells. In conclusion, despite ample evidence supporting CPT-induced carcinoma cell apoptosis, our study clearly shows that CPT fails to show any proapoptotic effects in HaCaT cells, even though it enhanced TRAIL receptor 1/2 expression and inhibited the expression of TNF-alpha-induced antiapoptotic proteins. Taken together, this study demonstrates that CPT fails to block the activity of TNF-alpha. With respect to the NE-kappa B-activating role of CPT, we suggest that the benefit of CPT in the treatment of psoriasis should be reevaluated. Copyright (C) 20125. Karger AG, Basel