A novel cantharidin analog N-benzylcantharidinamide reduces the expression of MMP-9 and invasive potentials of Hep3B via inhibiting cytosolic translocation of HuR.

Abstract

Invasion and metastasis are major causes of malignant tumor-associated mortality. The present study aimed to investigate the molecular events underlying inhibitory effect of N-benzylcantharidinamide, a novel synthetic analog of cantharidin, on matrix metalloproteinase-9 (MMP-9)-mediated invasion in highly metastatic hepatocellular carcinoma Hep3B cells. In this investigation, among six analogs of cantharidin, only N-benzylcantharidinamide has the inhibitory action on MMP-9 expression at non-toxic dose. The MMP-9 expression and invasion of Hep3B cells were significantly suppressed by treatment of N-benzylcantharidinamide in a dose-dependent manner. On the other hand, the transcriptional activity of MMP-9 promoter and nuclear levels of NF-κB and AP-1 as the main transcriptional factors inducing MMP-9 expression were not affected by it although the level of MMP-9 mRNA was reduced by treatment of N-benzylcantharidinamide. Interestingly, the stability of MMP-9 mRNA was significantly reduced by N-benzylcantharidinamide-treatment. In addition, the cytosolic translocation of human antigen R (HuR), which results in the increase of MMP-9 mRNA stability through interaction of HuR with 3'-untranslated region of MMP-9 mRNA, was suppressed by treatment of N-benzylcantharidinamide, in a dose-dependent manner. Taken together, it was demonstrated, for the first time, that N-benzylcantharidinamide suppresses MMP-9 expression by reducing HuR-mediated MMP-9 mRNA stability for the inhibition of invasive potential in highly metastatic Hep3B cells.

• Authors: Ji-Yeon Lee, Tae-Wook Chung, Hee-Jung Choi, Chang Hyun Lee, Jae Soon Eun, Young Taek Han, Jun-Yong Choi, So-Yeon Kim, Chang-Woo Han, Han-Sol Jeong, Ki-Tae Ha
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 447 Issue 2 Pg. 371-7 (May 02 2014) ISSN: 1090-2104 [Electronic] United States
• PMID: 24735540 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• ELAV Proteins
• Imides
• N-benzylcantharidinamide
• Protease Inhibitors
• RNA, Messenger
• MMP9 protein, human
• Matrix Metalloproteinase 9
• Cantharidin

Topics

• Cantharidin (analogs & derivatives, chemistry, pharmacology)
• Carcinoma, Hepatocellular (enzymology, pathology)
• Cell Line, Tumor
• Cytosol (metabolism)
• ELAV Proteins (metabolism)
• Humans
• Imides (chemistry, pharmacology)
• Liver Neoplasms (enzymology, pathology)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Neoplasm Invasiveness
• Promoter Regions, Genetic (drug effects)
• Protease Inhibitors (chemistry, pharmacology)
• Protein Transport (drug effects)
• RNA Stability (drug effects)
• RNA, Messenger (chemistry, genetics)