Curcumin inhibits lung cancer cell invasion and metastasis through the tumor suppressor HLJ1
Curcumin inhibits lung cancer cell invasion and metastasis through the tumor suppressor HLJ1
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DOI：
10.1158/0008-5472.can-07-6734
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发表时间：
2008-09-15
期刊：
影响因子：
11.2
通讯作者：
Yang, Pan-Chyr
中科院分区：
文献类型：
--
作者：
Chen, Huei-Wen;Lee, Jen-Yi;Yang, Pan-Chyr
姜黄素（二阿魏酰甲烷）是香料姜黄的活性成分，具有多种抗肿瘤活性。在这项研究中，我们发现姜黄素可以通过激活抑癌基因DnaJ样热休克蛋白40（HLJ1）来抑制癌细胞的侵袭和转移。姜黄素（1-20 μmol/L）处理的人肺腺癌细胞（CL1-5）表现出浓度依赖性细胞迁移、侵袭和转移能力的降低，这与HLJ1表达增加有关。通过 siRNA 敲低 HLJ1 表达能够逆转姜黄素诱导的体外和体内抗侵袭和抗转移作用。荧光素酶报告基因检测中的 HLJ1 启动子和增强子显示，姜黄素通过 HLJ1 增强子内的激活蛋白 (AP-1) 位点转录上调 HLJ1 表达。 junD 是 AP-1 成分之一，姜黄素 (1-20 mu mol/L) 以浓度和时间依赖性方式显着上调 junD。 junD表达的敲低可以部分减少姜黄素诱导的HLJ1激活并减弱姜黄素的抗侵袭作用，表明junD似乎参与姜黄素诱导的HLJ1表达。姜黄素能够诱导 c-Jun NH2 激酶 (JNK) 磷酸化，而 JNK 抑制剂 (SP-600125) 可以减弱姜黄素诱导的 JunD 和 HLJ1 表达。姜黄素激活 HLJ1 进一步导致 E-钙粘蛋白上调并抑制癌细胞侵袭。我们的结果表明，姜黄素通过激活 JNK/JunD 通路诱导 HLJ1，并通过调节 E-钙粘蛋白的表达来抑制肺癌细胞的侵袭和转移。这是一种新的机制，支持姜黄素在抗癌症转移治疗中的应用。
Curcumin (diferuloylmethane) is an active component of the spice turmeric and has a diversity of antitumor activities. In this study, we found that curcumin can inhibit cancer cell invasion and metastasis through activation of the tumor suppressor DnaJ-like heat shock protein 40 (HLJ1). Human lung adenocarcinoma cells (CL1-5) treated with curcumin (1-20 mu mol/L) showed a concentration-dependent reduction in cell migration, invasion, and metastatic ability, and this was associated with increased HLJ1 expression. Knockdown of HLJ1 expression by siRNA was able to reverse the curcumin-induced anti-invasive and antimetastasis effects in vitro and in vivo. The HLJ1 promoter and enhancer in a luciferase reporter assay revealed that curcumin transcriptionally up-regulates HLJ1 expression through an activator protein (AP-1) site within the HLJ1 enhancer. junD, one of the AP-1 components, was significantly up-regulated by curcumin (1-20 mu mol/L) in a concentration- and time-dependent manner. Knockdown of junD expression could partially reduce the curcumin-induced HLJ1 activation and diminish the anti-invasive effect of curcumin, indicating that junD would seem to be involved in curcumin-induced HLJ1 expression. Curcumin was able to induce c-Jun NH2-kinase (JNK) phosphorylation, whereas the JNK inhibitor (SP-600125) could attenuate curcumin-induced JunD and HLJ1 expression. Activation of HLJ1 by curcumin further leads to up-regulation of E-cadherin and a suppression of cancer cell invasion. Our results show that curcumin induces HLJ1, through activation of the JNK/JunD pathway, and inhibits lung cancer cell invasion and metastasis by modulating E-cadherin expression. This is a novel mechanism and supports the application of curcumin in anti-cancer metastasis therapy.