Mechanisms of apoptosis induced by the synthetic retinoid CD437 in human non-small cell lung carcinoma cells
Mechanisms of apoptosis induced by the synthetic retinoid CD437 in human non-small cell lung carcinoma cells
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DOI：
10.1038/sj.onc.1202543
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发表时间：
1999-04-08
期刊：
影响因子：
8
通讯作者：
Lotan, R
中科院分区：
文献类型：
--
作者：
Sun, SY;Yue, P;Lotan, R
新合成的维甲酸6-[3-（1-金刚烷基）-4-羟基苯基]-2-萘甲酸（CD 437）已显示在多种肿瘤细胞系中诱导凋亡，包括对天然全反式视黄酸和许多合成的受体选择性类视黄酸具有抗性的人非小细胞肺癌（NSCLC）细胞，尽管这种作用的机制尚未阐明，在本研究中，我们分析了CD 437在两种人NSCLC细胞系中诱导凋亡的机制：具有野生型p53的H460和具有突变型p53的H1792。两种细胞系在暴露于CD 437后均发生凋亡，尽管具有野生型p53的细胞系（H460）对诱导凋亡更敏感，但CD 437增加两种细胞系中的半胱天冬酶活性，然而，这种作用在H460细胞中更明显，半胱天冬酶抑制剂（Z-DEVD-FMK和Z-VAD-FMK）抑制两种细胞系中CD 437诱导的CPP 32样caspase活化和凋亡，CD 437诱导p53基因及其靶基因p21、Bas的表达，和Killer/DR 5，仅在H460细胞中。这些结果表明，CD 437诱导的细胞凋亡在表达野生型p53的NSCLC细胞中更广泛，可能是由于p53调节基因Killer/DR 5和Bar的参与，尽管CD 437也可以通过p53非依赖性机制诱导细胞凋亡。CD 437诱导的细胞凋亡的两种途径似乎都涉及CPP 32样caspase的激活。
The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) has been shown to induce apoptosis in various tumor cell lines including human non-small cell lung carcinoma (NSCLC) cells, which are resistant to the natural all-trans retinoic acid and to many synthetic receptor-selective retinoids, Although the mechanism of this effect was not elucidated, it was found to be independent of nuclear retinoid receptors, In the present study, we analysed the mechanisms by which CD437 induces apoptosis in two human NSCLC cell lines: H460 with wild-type p53 and H1792 with mutant p53. Both cell lines underwent apoptosis after exposure to CD437, although the cell line with wild-type p53 (H460) was more sensitive to the induction of apoptosis, CD437 increased the activity of caspase in both cell lines, however, the effect was much more pronounced in the H460 cells, The caspase inhibitors (Z-DEVD-FMK and Z-VAD-FMK) suppressed CD437-induced CPP32-like caspase activation and apoptosis in both cell lines, CD437 induced the expression of the p53 gene and its target genes, p21, Bas, and Killer/DR5, only in the H460 cells. These results suggest that CD437-induced apoptosis is more extensive in NSCLC cells that express wild-type p53, possibly due to the involvement of the p53 regulated genes Killer/DR5, and Bar although CD437 can also induce apoptosis by means of a p53-independent mechanism. Both pathways of CD437-induced apoptosis appear to involve activation of CPP32-like caspase.