Selective inhibition of cyclooxygenase-2 inhibits colon cancer cell adhesion to extracellular matrix by decreased expression of beta1 integrin.
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.
Yazawa
Kentaro
K
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
Tsuno
Nelson H
NH
Kitayama
Joji
J
Kawai
Kazushige
K
Okaji
Yurai
Y
Asakage
Masahiro
M
Sunami
Eiji
E
Kaisaki
Shoichi
S
Hori
Nobukazu
N
Watanabe
Toshiaki
T
Takahashi
Koki
K
Nagawa
Hirokazu
H
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
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
J Biol Chem. 1998 May 29;273(22):14030-6
9593754
Lancet Oncol. 2003 Oct;4(10):605-15
14554238
Carcinogenesis. 1998 Dec;19(12):2195-9
9886578
Int J Cancer. 2001 Mar 15;91(6):894-9
11275997
J Cell Physiol. 1997 Dec;173(3):361-70
9369949
Clin Exp Metastasis. 2003;20(7):577-84
14669788
Int J Cancer. 2005 Feb 10;113(4):541-8
15472909
Trends Biochem Sci. 2000 Aug;25(8):388-91
10916159
Curr Opin Cell Biol. 1996 Oct;8(5):724-30
8939661
Exp Cell Res. 2003 Oct 1;289(2):342-51
14499635
Gastroenterology. 2002 Oct;123(4):1151-62
12360478
Nat Med. 2001 Sep;7(9):1041-7
11533708
Br J Cancer. 1999 Dec;81(8):1274-9
10604722
Int J Cancer. 2001 Aug 15;93(4):497-506
11477553
J Cell Physiol. 1998 Dec;177(4):618-27
10092214
Cancer Sci. 2003 Mar;94(3):253-8
12824918
J Clin Invest. 1997 May 1;99(9):2254-9
9151799
Br J Surg. 2003 Sep;90(9):1055-67
12945071
Cancer Detect Prev. 2004;28(2):127-42
15068837
Br J Cancer. 2004 Feb 9;90(3):712-9
14760389
Anticancer Res. 2003 Jan-Feb;23(1A):245-9
12680220
Cell. 1992 Apr 3;69(1):11-25
1555235
Cancer. 1997 Oct 15;80(8 Suppl):1529-37
9362419
Int J Cancer. 2002 Aug 10;100(5):515-9
12124799