Cyclooxygenase-2 induction by arsenite is through a nuclear factor of activated T-cell-dependent pathway and plays an antiapoptotic role in Beas-2B cells
Cyclooxygenase-2 induction by arsenite is through a nuclear factor of activated T-cell-dependent pathway and plays an antiapoptotic role in Beas-2B cells
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DOI：
10.1074/jbc.m600751200
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发表时间：
2006-08-25
影响因子：
4.8
通讯作者：
Huang, Chuanshu
中科院分区：
文献类型：
--
作者：
Ding, Jin;Li, Jingxia;Huang, Chuanshu
亚砷酸盐是一种众所周知的类金属致癌物，流行病学证据表明它与肺癌发病率的增加有关。然而，其致癌作用的机制仍不清楚。目前的研究表明，暴露于亚砷酸盐的人支气管上皮细胞（Beas-2B）导致环氧合酶（考克斯）-2，炎症和肿瘤促进的重要介质的显着诱导。Beas-2 B细胞暴露于亚砷酸盐也导致活化T细胞的核因子（NFAT）的显著反式激活，但不导致活化蛋白-1（AP-1）和NF κ B的反式激活，这表明NFAT而不是AP-1或NF κ B参与了Beas-2 B细胞对亚砷酸盐暴露的反应。此外，我们发现，无论是化学抑制剂，NFAT的显性负突变体，或NFAT 3小干扰RNA的NFAT途径的抑制导致考克斯-2诱导的损害，并引起细胞凋亡的Beas-2B细胞暴露于亚砷酸盐。在考克斯-2启动子区域中-111至+65之间的两个推定的NFAT结合位点的定点突变消除了亚砷酸盐诱导的考克斯-2转录活性，证实了考克斯-2启动子区域中的这两个NFAT结合位点对于亚砷酸盐诱导考克斯-2是关键的。此外，通过考克斯-2特异性小干扰RNA敲低考克斯-2表达也导致砷暴露后Beas-2B细胞凋亡增加。总之，我们的研究结果表明，考克斯-2诱导亚砷酸盐是通过NFAT 3依赖性和AP-1或NF κ B的非依赖性途径，并在拮抗亚砷酸盐诱导的人支气管上皮细胞Beas-2B细胞的细胞凋亡中起着至关重要的作用。
Arsenite is a well known metalloid human carcinogen, and epidemiological evidence has demonstrated its association with the increased incidence of lung cancer. However, the mechanism involved in its lung carcinogenic effect remains obscure. The current study demonstrated that exposure of human bronchial epithelial cells (Beas-2B) to arsenite resulted in a marked induction of cyclooxygenase (COX)-2, an important mediator for inflammation and tumor promotion. Exposure of the Beas-2B cells to arsenite also led to significant transactivation of nuclear factor of activated T-cells (NFAT), but not activator protein-1 (AP-1) and NF kappa B, suggesting that NFAT, rather than AP-1 or NF kappa B, is implicated in the responses of Beas-2B cells to arsenite exposure. Furthermore, we found that inhibition of the NFAT pathway by either chemical inhibitors, dominant negative mutants of NFAT, or NFAT3 small interference RNA resulted in the impairment of COX-2 induction and caused cell apoptosis in Beas-2B cells exposed to arsenite. Site- directed mutation of two putative NFAT binding sites between -111 to +65 in the COX-2 promoter region eliminated the COX-2 transcriptional activity induced by arsenite, confirming that those two NFAT binding sites in the COX-2 promoter region are critical for COX-2 induction by arsenite. Moreover, knockdown of COX-2 expression by COX-2-specific small interference RNA also led to an increased cell apoptosis in Beas-2B cells upon arsenite exposure. Together, our results demonstrate that COX-2 induction by arsenite is through NFAT3-dependent and AP-1- or NF kappa B-independent pathways and plays a crucial role in antagonizing arsenite-induced cell apoptosis in human bronchial epithelial Beas-2B cells.