title: Magnolol down-regulates HER2 gene expression, leading to inhibition of HER2-mediated metastatic potential in ovarian cancer cells.
abstract: Overexpression of the HER2 oncogene contributes to tumor cell invasion, metastasis and angiogenesis and correlates with poor prognosis. Magnolol has been reported to exhibit anti-tumor activities. However, the molecular mechanism of action of magnolol has not been investigated in HER2-positive cancer cells. Therefore, we examined the anti-cancer effects of magnolol on HER2-overexpressing ovarian cancer cells. Magnolol treatment caused a dose-dependent inhibition of HER2 gene expression at the transcriptional level, potentially in part through suppression of NF-κB activation. Treatment of HER2-overexpressing ovarian cancer cells with magnolol down-regulated the HER2 downstream PI3K/Akt signaling pathway, and suppressed the expression of downstream target genes, vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2) and cyclin D1. Consistently, magnolol-mediated inhibition of MMP2 activity could be prevented by co-treatment with epidermal growth factor. Migration assays revealed that magnolol treatment markedly reduced the motility of HER2-overexpressing ovarian cancer cells. Furthermore, magnolol-induced apoptosis in HER2-overexpressing ovarian cancer cells was characterized by the up-regulation of cleaved poly(ADP-ribose) polymerase (PARP) and activated caspase 3. These findings suggest that magnolol may act against HER2 and its downstream PI3K/Akt/mTOR-signaling network, thus resulting in suppression of HER2-mediated transformation and metastatic potential in HER2-overexpressing ovarian cancers. These results provide a novel mechanism to explain the anti-cancer effect of magnolol.
authors.affiliation: Department of Chemistry, Tamkang University, New Taipei, Taiwan, ROC. tcbc@mail.tku.edu.tw
authors.forename: Tzu-Chao
authors.initials: TC
authors.lastname: Chuang
authors.forename: Shih-Chung
authors.initials: SC
authors.lastname: Hsu
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Cheng
authors.forename: Wei-Syun
authors.initials: WS
authors.lastname: Shao
authors.forename: Kuohui
authors.initials: K
authors.lastname: Wu
authors.forename: Guan-Shiun
authors.initials: GS
authors.lastname: Fang
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Ou
authors.forename: Vinchi
authors.initials: V
authors.lastname: Wang
mesh_terms: D001713:Biphenyl Compounds / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018734:Genes, erbB-2 / Q000187:drug effects; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001713:Biphenyl Compounds; D053148:Caspase 3; D019938:Cyclin D1; D017705:Lignans; D019869:Phosphatidylinositol 3-Kinases; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C530104:CCND1 protein, human; C467484:VEGFA protein, human; C005498:magnolol; C546842:MTOR protein, human