Arsenic trioxide induces human pulmonary fibroblast cell death via the regulation of Bcl-2 family and caspase-8
Arsenic trioxide induces human pulmonary fibroblast cell death via the regulation of Bcl-2 family and caspase-8
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DOI：
10.1007/s11033-011-1218-z
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发表时间：
2012-04-01
影响因子：
2.8
通讯作者：
Kim, Suhn Hee
中科院分区：
文献类型：
--
作者：
Park, Woo Hyun;Kim, Suhn Hee
三氧化二砷（ATO; As2O3）可诱导包括肺癌细胞在内的多种癌细胞的凋亡细胞死亡。然而，ATO对正常原代肺细胞的毒理学作用知之甚少。在这项研究中，我们研究了ATO对人肺成纤维细胞（HPF）细胞生长抑制和死亡的影响。ATO在24 h抑制HPF细胞生长，IC50约为30-40 μ M，并诱导细胞死亡并伴有线粒体膜电位（MMP; Delta I-m）的丧失。因此，HPF细胞被认为对ATO的损伤具有很强的抵抗力。ATO增加p53蛋白的表达，降低Bcl-2蛋白的表达。这种药物在HPF细胞中激活了caspase-8，但没有激活caspase-3。Z-VAD（一种泛caspase抑制剂，15 μ M）没有显著降低ATO引起的细胞生长抑制、死亡和MMP （δ I-m）损失。此外，Bax或casase-8 siRNA可减轻ATO引起的HPF细胞死亡，而p53或caspase-3 siRNA不影响细胞死亡。综上所述，高剂量ATO通过调控Bcl-2家族和caspase-8诱导HPF细胞生长抑制和死亡。
Arsenic trioxide (ATO; As2O3) can induce apoptotic cell death in various cancer cells including lung cancer cells. However, little is known about the toxicological effects of ATO on normal primary lung cells. In this study, we investigated the cellular effects of ATO on human pulmonary fibroblast (HPF) cells in relation to cell growth inhibition and death. ATO inhibited HPF cell growth with an IC50 of approximately 30-40 mu M at 24 h and induced cell death accompanied by the loss of mitochondrial membrane potential (MMP; Delta I-m). Thus, HPF cells were considered to be very resistant to ATO insults. ATO increased the expression of p53 protein and decreased that of Bcl-2 protein. This agent activated caspase-8 but not caspase-3 in HPF cells. Z-VAD (a pan-caspase inhibitor; 15 mu M) did not significantly decrease cell growth inhibition, death and MMP (Delta I-m) loss by ATO. Moreover, administration of Bax or casase-8 siRNA attenuated HPF cell death by ATO whereas p53 or caspase-3 siRNAs did not affect cell death. In conclusion, HPF cells were resistant to ATO and higher doses of ATO induced the growth inhibition and death in HPF cells via the regulation of Bcl-2 family and caspase-8.