title: 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.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chung
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Department of Anatomy, College of Korean Medicine, Woosuk University, Wanju-gun, Jeonbuk, Republic of Korea.
authors.forename: Chang Hyun
authors.initials: CH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Woosuk University, Wanju-gun, Jeonbuk, Republic of Korea.
authors.forename: Jae Soon
authors.initials: JS
authors.lastname: Eun
authors.affiliation: College of Pharmacy, Woosuk University, Wanju-gun, Jeonbuk, Republic of Korea.
authors.forename: Young Taek
authors.initials: YT
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Korean Medicine Hospital, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea; Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Jun-Yong
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Korean Medicine Hospital, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Korean Medicine Hospital, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Han
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea. Electronic address: jhsol33@pusan.ac.kr.
authors.forename: Han-Sol
authors.initials: HS
authors.lastname: Jeong
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea; Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea. Electronic address: hagis@pusan.ac.kr.
authors.forename: Ki-Tae
authors.initials: KT
authors.lastname: Ha
mesh_terms: D002193:Cantharidin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism*; D051959:ELAV Proteins / Q000378:metabolism*; D006801:Humans; D007094:Imides / Q000737:chemistry / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics
chemical_list: D051959:ELAV Proteins; D007094:Imides; C000589737:N-benzylcantharidinamide; D011480:Protease Inhibitors; D012333:RNA, Messenger; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D002193:Cantharidin
keywords: Cancer; HuR; Invasion; MMP-9; N-Benzylcantharidinamide