Cisplatin induces apoptosis in oral squamous carcinoma cells by the mitochondria-mediated but not the NF-κB-suppressed pathway
Cisplatin induces apoptosis in oral squamous carcinoma cells by the mitochondria-mediated but not the NF-κB-suppressed pathway
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DOI：
10.1016/s1368-8375(02)00116-1
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发表时间：
2003-04-01
期刊：
影响因子：
4.8
通讯作者：
Sato, M
中科院分区：
文献类型：
--
作者：
Azuma, M;Tamatani, T;Sato, M
顺铂（CDDP）是一种有效的dna损伤抗癌药物，其细胞毒性作用是通过诱导细胞凋亡发挥的。然而，转录因子NF-KB的激活导致对细胞凋亡的保护。我们研究了CDDP诱导细胞凋亡的分子机制，包括NF-KB的抑制和caspase的激活。本研究以人口腔鳞癌细胞B88为研究对象。我们发现CDDP处理既不影响NF-KB活性，也不影响B88细胞中抗凋亡蛋白（包括TRAF-1、TRAF-2和cFLIP）的表达水平。然而，细胞色素c和Apaf-1两种凋亡分子在CDDP处理后细胞质中明显增加。此外，在CDDP处理后，检测到下游分子caspase-9和caspase-3的激活，这些分子导致线粒体介导的细胞凋亡。最后，凋亡也被清楚地观察到，通过激活caspase-3， PARP被切割。这些发现表明，CDDP通过线粒体介导的半胱天冬酶激活发挥其凋亡作用，而不是通过抑制抗凋亡蛋白后抑制NF-KB活性而激活半胱天冬酶。2003爱思唯尔科学有限公司版权所有。
Cisplatin (CDDP) is a potent DNA-damaging anticancer agent, and its cytotoxic action is exerted by the induction of apoptosis. However, activation of the transcription factor NF-KB results in protection against apoptosis. We examined the molecular mechanisms involved in the induction of apoptosis by CDDP as regards both suppression of NF-KB and activation of caspases. Human oral squamous carcinoma cells (B88) were employed in this study. We found that CDDP treatment affected neither NF-KB activity nor the expression levels of antiapoptotic proteins, including TRAF-1, TRAF-2, and cFLIP, in B88 cells. However, two apoptosome molecules, cytochrome c and Apaf-1, were significantly augmented in the cytoplasm by CDDP treatment. Further, the activation of caspase-9 and caspase-3, downstream molecules leading to mitochondria-mediated apoptosis, were detected after treatment with CDDP. Finally, apoptosis was also clearly observed, as evidenced by cleavage of PARP through the activation of caspase-3. These findings suggest that CDDP exerts its apoptotic action by the mitochondria-mediated activation of caspases but not by the activation of caspases due to the inhibition of NF-KB activity that follows the suppression of antiapoptotic proteins. (C) 2003 Elsevier Science Ltd. All rights reserved.