Curcumin inhibits lung cancer cell invasion and metastasis through the tumor suppressor HLJ1.
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 mumol/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 mumol/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 NH(2)-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.
Chen
Huei-Wen
HW
Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University,Taipei, Taiwan.
Lee
Jen-Yi
JY
Huang
Ji-Ying
JY
Wang
Chi-Chung
CC
Chen
Wan-Jiun
WJ
Su
Sheng-Fang
SF
Huang
Chia-Wen
CW
Ho
Chao-Chi
CC
Chen
Jeremy J W
JJ
Tsai
Meng-Feng
MF
Yu
Sung-Liang
SL
Yang
Pan-Chyr
PC
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003474:Curcumin / Q000494:pharmacology*; D050956:HSP40 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
D015820:Cadherins; C494650:DNAJB4 protein, human; D050956:HSP40 Heat-Shock Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D048670:MAP Kinase Kinase 4; D003474:Curcumin