Mitomycin C induces apoptosis via Fas/FasL dependent pathway and suppression.of IL-18 in cervical carcinoma cells
Mitomycin C induces apoptosis via Fas/FasL dependent pathway and suppression.of IL-18 in cervical carcinoma cells
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DOI：
10.1016/j.canlet.2005.05.043
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发表时间：
2006-06-08
期刊：
影响因子：
9.7
通讯作者：
Yoon, Do-Young
中科院分区：
文献类型：
--
作者：
Kang, Yun Hee;Lee, Kyung-Ae;Yoon, Do-Young
丝裂霉素 C (MMC) 作为一种抗癌药物应用相当广泛，因为它具有优于其他化疗化合物（包括顺铂、多西紫杉醇和洛伐他汀）的作用机制。在前期的研究中，我们建立了RSV-luc启动子分析系统，用于筛选针对HPV感染引起的宫颈癌的药物。然后，我们证明了卡铂 (CA)、顺铂 (CIS) 和 MMC 等抗癌药物可抑制 HPV E6 激活的 RSV 启动子活性。在这些研究中，我们重点研究了 MMC 处理的宫颈癌细胞系的凋亡机制，尤其是 SiHa/pRSV-luc (KCTC 0427BP) 和 SiHa。 DNA 片段化分析和 TUNEL 染色显示，MMC 和 CIS（而非 CA）导致细胞凋亡。 MMC 处理以不依赖 p53 的方式诱导 E6 癌基因和 IL-18 表达减少。 MMC 还增加 FasL 表达并诱导 caspase-8 和 -3 的加工。我们的结果表明，MMC 通过 caspase-8 和 -3 加工，以 Fas/FasL 依赖性方式诱导 SiHa/pRSV-luc 和 SiHa 细胞凋亡。 MMC 还抑制相同细胞中 IL-18 的表达。 MMC 还下调 I kappa B 表达，并上调 p65 表达。这些结果表明MMC不仅通过caspase-8和-3依赖性Fas/FasL途径诱导细胞凋亡，而且还通过调节NF-κB活性和IL-18表达。 (c) 2005 Elsevier Ireland Ltd. 保留所有权利。
Mitomycin C (MMC) is used fairly widely as an anticancer drug, as it possesses mechanisms of action which are preferable to other chemotherapeutic compounds, including cisplatin, docetaxel, and lovastatin. In the previous study, we established the RSV-luc promoter analysis system, which is used to screen drugs against cervical carcinomas caused by HPV infection. We then demonstrated the repression of HPV E6-activated RSV promoter activity by anticancer agents such as carboplatin (CA), cisplatin (CIS), and MMC. In these studies, we focused on the investigation of apoptotic mechanisms in MMC-treated cervical carcinoma cell lines, most notably SiHa/pRSV-luc (KCTC 0427BP) and SiHa. DNA fragmentation assays and TUNEL staining revealed that MMC and CIS, but not CA, resulted in apoptosis. MMC treatment induced a reduction in the expressions of the E6 oncogene and IL-18, in a p53-independent manner. MMC also increased FasL expression and induced the processing of caspases-8 and -3. Our results indicated that MMC induced apoptosis in SiHa/pRSV-luc and SiHa cells via caspase-8 and -3 processing, in a Fas/FasL-dependent manner. MMC also suppressed the expression of IL-18 in the same cells. MMC also down-regulated I kappa B expression, and up-regulated p65 expression. These results suggest that MMC induces apoptosis, not only through caspase-8 and -3 dependent Fas/FasL pathway, but also via the regulation of NF-kappa B activity and IL-18 expression. (c) 2005 Elsevier Ireland Ltd. All rights reserved.