title: Inhibition of matrix metalloproteinase-9 expression by docosahexaenoic acid mediated by heme oxygenase 1 in 12-O-tetradecanoylphorbol-13-acetate-induced MCF-7 human breast cancer cells.
abstract: Matrix metalloproteinase-9 (MMP-9) plays a crucial role in tumor metastasis. Previous studies showed that polyunsaturated fatty acids exhibit an anti-cancer effect in various human carcinoma cells, but the effect of docosahexaenoic acid (DHA) and linoleic acid (LA) on metastasis of breast cancer cells is not fully clarified. We studied the anti-metastasis potential of DHA and LA in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MCF-7 cells. We found that TPA (100 ng/ml) induced MMP-9 enzyme activity both dose- and time-dependently, and 200 μM DHA and LA significantly inhibited MMP-9 mRNA and protein expression, enzyme activity, cell migration, and invasion. Treatment with PD98059 (10 μM), wortmannin (10 μM), and GF109203X (0.5 μM) decreased TPA-induced MMP-9 protein expression and enzyme activity. TPA-induced activation of ERK1, Akt, and PKCδ was attenuated by DHA, whereas LA attenuated only ERK1 activation. GF109203X also suppressed ERK1 activation. EMSA showed that DHA, LA, PD98059, and wortmannin decreased TPA-induced NF-κB and AP-1 DNA-binding activity. Furthermore, DHA rather than LA dose-dependently increased HO-1 expression. HO-1 siRNA alleviated the inhibition by DHA of TPA-induced MMP-9 protein expression and enzyme activity in MCF-7 cells, and HO-1 knockdown reversed the DHA inhibition of cell migration. These results suggest that DHA and LA have both similar and divergent signaling pathways in the suppression of TPA-induced MCF-7 metastasis.
authors.affiliation: Department of Nutrition, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Che-Yi
authors.initials: CY
authors.lastname: Chao
authors.forename: Li-Lin
authors.initials: LL
authors.lastname: Lin
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Lu
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Liu
authors.forename: Chong-Kuei
authors.initials: CK
authors.lastname: Lii
authors.forename: Chien-Chun
authors.initials: CC
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D061986:MCF-7 Cells; D008301:Maleimides / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D013997:Time Factors; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D002273:Carcinogens; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D004281:Docosahexaenoic Acids; D051547:Heme Oxygenase-1; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin