title: Selective inhibition of cyclooxygenase-2 inhibits colon cancer cell adhesion to extracellular matrix by decreased expression of beta1 integrin.
abstract: High level expression of cyclooxygenase (COX)-2 is reported in 80-90% of colorectal adenocarcinomas. In the recent years, selective inhibitors of COX-2 have been developed, and are shown to effectively protect against cancer development and progression. Colon cancer cells, as well as the epithelial cells in general, are dependent on appropriate interactions with the extracellular matrix (ECM) proteins to achieve a number of important functions, such as proliferation, differentiation, invasion and survival. These interactions are mediated via a family of cell-surface receptors called integrins, which interact with cytoskeletal proteins on the cytoplasmic side of the plasma membrane and thereby provide a link between the ECM and the cytoskeleton. In the present study, a high-COX-2 (high level COX-2 expression) colon cancer cell line, HT-29, and a low-COX-2 (low level COX-2 expression), DLD-1, were used to investigate the anticolon cancer effect of the selective COX-2 inhibitor, JTE-522. Moreover, to clarify its mechanisms of action, we focused especially on the ability to adhere to and to migrate on ECM. We could clearly demonstrate that, in addition to the decrease of the proliferative activity, JTE-522 caused a dose-dependent decrease in both the ability of colon cancer cells to adhere to and to migrate on ECM. These effects were, at least in part, dependent on the down-regulation of beta1-integrin expression, which was evident in HT-29, the high-COX-2 colon cancer cells, but not the low-COX-2, DLD-1. In addition, prostaglandin E2 almost completely reversed the effect of JTE-522, strongly suggesting the involvement of a COX-2-dependent pathway. In conclusion, for the first time, we could demonstrate the down-regulation of beta1 integrin caused by COX-2 inhibition, with consequent impairment of the ability of cancer cells to adhere to and to migrate on ECM, which are crucial steps for cancer metastases to develop.
authors.affiliation: Department of Surgical Oncology, Faculty of Medical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. kyazawa-tky@umin.ac.jp
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yazawa
authors.forename: Nelson H
authors.initials: NH
authors.lastname: Tsuno
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
authors.forename: Kazushige
authors.initials: K
authors.lastname: Kawai
authors.forename: Yurai
authors.initials: Y
authors.lastname: Okaji
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asakage
authors.forename: Eiji
authors.initials: E
authors.lastname: Sunami
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kaisaki
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Hori
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Koki
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Nagawa
mesh_terms: D001557:Benzenesulfonates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008565:Membrane Proteins; D010080:Oxazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
chemical_list: D001557:Benzenesulfonates; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D019012:Integrin beta1; D008565:Membrane Proteins; D010080:Oxazoles; D011451:Prostaglandin-Endoperoxide Synthases; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C496540:PTGS2 protein, human
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