title: p38α MAPK mediates 17β-estradiol inhibition of MMP-2 and -9 expression and cell migration in human lovo colon cancer cells.
abstract: Epidemiological studies demonstrate that the incidence and mortality rates of colorectal cancer in women are lower than in men. However, it is unknown if 17β-estradiol (E(2)) treatment is sufficient to inhibit cell proliferation and cell migration in human colon cancer cells. Up-regulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. In the present study, we treated human LoVo colon cancer cells with E(2) to explore whether E(2) down-regulates cell proliferation and migration, and to identify the precise molecular and cellular mechanisms behind the down-regulatory responses. Here, we found that E(2) treatment decreased cell proliferation and cell cycle-regulating factors such as cyclin A, cyclin D1 and cyclin E. At the same time, E(2) significantly inhibited cell migration and migration-related factors such as uPA, tPA, MMP-2, and MMP-9. However, E(2) treatment showed no effects on upregulating expression of plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4). After administration of inhibitors including QNZ (NFκB inhibitor), LY294002 (Akt activation inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor) or SP600125 (JNK1/2 inhibitor), E(2) -downregulated cell migration and expression of MMP-2 and MMP-9 in LoVo cells is markedly inhibited only by p38 MAPK inhibitors, SB203580. Application of specific target gene siRNA (ERα, ERβ, p38α, and p38β) to LoVo cells further confirmed that p38 MAPK mediates E(2) /ERs inhibition of MMP-2 and -9 expression and cell motility in LoVo cells. Collectively, these results suggest that E(2) treatment down-regulates cell proliferation by modulating the expression of cyclin A, cyclin D1 and cyclin E. E(2) treatment simultaneously impaired cell migration by inhibiting the expression of uPA, tPA, MMP-2, and MMP-9 through E(2) /ERs - p38α MAPK signaling pathway in human LoVo colon cancer cells.
authors.affiliation: Division of Colorectal Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Hsu
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Liu
authors.forename: Chia-Yao
authors.initials: CY
authors.lastname: Shen
authors.forename: Yi-Jyun
authors.initials: YJ
authors.lastname: Chen
authors.forename: Li-Mien
authors.initials: LM
authors.lastname: Chen
authors.forename: Wu-Hsien
authors.initials: WH
authors.lastname: Kuo
authors.forename: Yueh-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Ray-Jade
authors.initials: RJ
authors.lastname: Chen
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Tsai
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D019925:Cyclin A; D019927:Cyclin E; D019938:Cyclin D1; D004958:Estradiol; D051057:Proto-Oncogene Proteins c-akt; D048308:Mitogen-Activated Protein Kinase 14; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9