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Curcumin Inhibits Lung Cancer Cell Invasion and Metastasis through the Tumor Suppressor HLJ1

¹ Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, ² Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, and ³ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; ⁴ Graduate Institute of Basic Medicine, Fu Jen Catholic University, Taipei, Taiwan; and ⁵ Institute of Biomedical Science and Molecular Biology, College of Life Sciences, National Chung-Hsing University, Taichung, Taiwan; and ⁶ Department of Molecular Biotechnology, Da-Yeh University, Changhua, Taiwan

Requests for reprints: Pan-Chyr Yang, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, No.7, Chung-Shan South Road, Taipei, 100, Taiwan. Phone: 886-2-23562185; Fax: 886-2-23224793; E-mail: pcyang{at}ntu.edu.tw and Huei-Wen Chen, 155, Li-Nong Street, Taipei, Taiwan. E-mail: hwchen{at}ym.edu.tw.

Key Words: curcumin • HLJ1 • JNK • JunD • E-cadherin • invasion • metastasis

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 µmol/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 µmol/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. [Cancer Res 2008;68(18):7428–38]