Sodium 4-phenylbutyrate induces apoptosis of human lung carcinoma cells through activating JNK pathway.
Sodium 4-phenylbutyrate induces apoptosis of human lung carcinoma cells through activating JNK pathway.
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4-苯基丁酸钠通过激活JNK通路诱导人肺癌细胞凋亡。
DOI：
10.1002/jcb.20173
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Yu,Qiang
中科院分区：
文献类型：
--
作者：
Zhang,Xing;Wei,Lin;Yang,Yu;Yu,Qiang
4-苯基丁酸钠（PB）已用于治疗尿素循环缺陷多年。最近，它已被证明在某些恶性肿瘤中引起细胞分化、生长停滞和凋亡。本文分析了PB对人肺癌细胞的作用。PB对不同肺癌细胞具有不同的作用模式，诱导NCI-H460和NCI-H1792细胞凋亡，导致A549和SK-LU-1细胞G1期阻滞，但对非转化支气管上皮细胞系HBE 4-E6/E7无影响。我们研究了MAP激酶家族成员、细胞外信号调节激酶（ERK）、JNK和p38丝裂原活化蛋白激酶（MAPK）以及其他重要的细胞存活信号分子在PB诱导的细胞凋亡中的作用。我们观察了PB对肺癌细胞JNK和ERK的激活作用。JNK仅在两种凋亡细胞中被激活，而ERK在凋亡和生长停滞细胞中均被激活，表明凋亡和JNK激活之间存在相关性。JNK抑制剂和JNK RNA干扰（RNAi）均抑制PB诱导的细胞凋亡，而MEK抑制剂则无此作用，支持PB通过激活JNK诱导细胞凋亡。PB诱导的JNK活化和诱导细胞凋亡需要从头蛋白合成。然而，已知的JNK上游激活剂，即Fas/Fas配体、肿瘤坏死因子（TNF）-α、TNF-β和TRAIL的产生不会被PB处理改变。因此，PB通过一种未鉴定的细胞类型特异性机制激活JNK。了解这一机制对治疗癌症患者的PB具有重要的临床价值。© 2004 Wiley利斯公司
Sodium 4‐phenylbutyrate (PB) has been used in the therapy of urea cycle defects for many years. Recently, it has been shown to cause cellular differentiation, growth arrest, and apoptosis in certain malignancies. We have analyzed the effects of PB on human lung carcinoma cells. PB has distinct patterns of effects on different lung carcinoma cells, inducing apoptosis in NCI‐H460 and NCI‐H1792 cells, causing G1 arrest in A549 and SK‐LU‐1 cells, but having no effect on a non‐transformed bronchial epithelial cell line HBE4‐E6/E7. We investigated the role of MAP kinase family members, extracellular signal‐regulated kinase (ERK), JNK, and p38 mitogen‐activated protein kinase (MAPK), as well as other important cell survival signaling molecules in PB‐induced apoptosis. We observed activation of JNK and ERK by PB in the lung cancer cells. JNK was activated only in the two apoptotic cells, whereas ERK was activated in both the apoptotic and the growth‐arrested cells, demonstrating a correlation between apoptosis and activation of JNK in response to PB. Both JNK inhibitor and JNK RNA interference (RNAi) inhibited PB‐induced apoptosis, whereas MEK inhibitor did not, supporting that apoptosis induced by PB is through activation of JNK. De novo protein synthesis is required for the PB‐induced JNK activation and induction of apoptosis. However, the production of known upstream activators of JNK, namely Fas/Fas ligand, tumor necrosis factor (TNF)‐α, TNF‐β, and TRAIL, are not altered by PB treatment. Therefore, PB activates JNK through an unidentified and cell type‐specific mechanism. Understanding of this mechanism is of therapeutic value in treating cancer patients with PB. © 2004 Wiley‐Liss, Inc.