title: 4-Hydroxybutenolide impairs cell migration, and invasion of human oral cancer SCC-4 cells via the inhibition of NF-κB and MAPK signaling pathways.
abstract: 4-Hydroxybutenolide (K87), a synthetic compound from furfuryl alcohol via photooxidation, was used to investigate whether it can inhibit mobility, migration and invasion of SCC-4 human oral cancer cells in vitro. Cell viability was measured by flow cytometric assay, the enzymatic activities of MMP-2/9 were assayed by gelatin zymography analysis, the protein levels were assayed by western blotting, confocal laser microscopy and EMSA assay, and the gene expression of MMP-2/-7, FAK and ROCK1 mRNA were assayed by PCR. K87 decreased the percentage of viable cells in dose-dependent manner. K87 suppressed cell mobility, migration and invasion of SCC-4 cells dose-dependently. K87 inhibited the enzymatic activities of MMP-2/9 of SCC-4 cells. Western blot analysis revealed that K87 decreased the protein levels in NF-κBp65, COX-2, ROCK1 and Rho A, MMP-1, -2,- 7, -9, VEGF, GRB2, SOS1, PI3K, PKC, PERK, p-PERK, FAK, MEKK3, MKK7, ERK1/2, JNK1/2, p-p38, p38, p-c-Jun, AKT, TIMP2, but increased the protein levels of iNOS, Ras, IRE-1α, p-c-JNK, p-AKT(308), p-AKT(473) and TIMP1. Results from PCR indicated that K87 inhibited the gene expression of MMP-2/-7, FAK and ROCK1 mRNA. Furthermore, confocal laser microscopy was used to confirm that K87 inhibited the translocation of RHOA and ROCK1 in SCC-4 cells. EMSA assay also show that K87 suppressed the nuclear activation of NF-κB and these effects are time-dependent. Western blotting assay indicated that expression of NF-κBp105, NF-κBp50 and NF-κBp65 proteins were decreased and these effects are time-dependent. Based on these observations, we suggest that K87 may be used as a potential agent for anticancer metastasis of human oral cancer in the future.
authors.affiliation: School of Dentist, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Fu-Shun
authors.initials: FS
authors.lastname: Yu
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Meng-Liang
authors.initials: ML
authors.lastname: Lin
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Department of Physiology, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Huang
authors.affiliation: Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Yueh-Hsiung
authors.initials: YH
authors.lastname: Kuo
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung
mesh_terms: D015107:4-Butyrolactone / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D015107:4-Butyrolactone