title: Inhibition of cyclooxygenase-2-mediated matriptase activation contributes to the suppression of prostate cancer cell motility and metastasis.
abstract: Chronic inflammation plays an important role in cancer development and progression. Cyclooxygenases-2 (COX-2) is a key enzyme in generating prostaglandins causing inflammation, is often found to be overexpressed in prostate cancer (PCa) and is correlated with PCa cell invasion and metastasis. We aim to investigate the molecular mechanism of how COX-2 promotes PCa cell invasion and metastasis and to evaluate the effect of COX-2 inhibitors in a selected model of PCa progression. Our results showed that the expression of COX-2 and Interleukin 1β (IL-1β) was upregulated in highly invasive PCa cells and was correlated with the activated levels of membrane-anchored serine protease matriptase. The expression levels of COX-2 were increased and were correlated with matriptase levels in PCa specimens. Moreover, results showed that COX-2 overexpression or a COX-2 product Prostaglandin E2(PGE2) caused an increase in matriptase activation and PCa cell invasion, whereas COX-2 silencing antagonized matriptase activation and cell invasion. In addition, the inhibition of COX-2-mediated matriptase activation by Celebrex and sulindac sulfide suppressed the androgen-independent and COX2-overexpressing PCa PC-3 cell invasion, tumor growth and lung metastasis in an orthotopic xenograft model. Our results indicate that COX-2/matriptase signaling contributes to the invasion, tumor growth and metastasis of COX-2-overexpressing and androgen-independent PCa cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Ko
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: S-W
authors.initials: SW
authors.lastname: Lan
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: T-S
authors.initials: TS
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: P-F
authors.initials: PF
authors.lastname: Lai
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: T-W
authors.initials: TW
authors.lastname: Hsu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Bureau of Investigation, Ministry of Justice, Taipei, Taiwan.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Shyu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: S-R
authors.initials: SR
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: H-H
authors.initials: HH
authors.lastname: Lin
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: P-W
authors.initials: PW
authors.lastname: Hsiao
authors.affiliation: Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: H-P
authors.initials: HP
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: M-S
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000818:Animals; D000068579:Celecoxib / Q000494:pharmacology / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D012697:Serine Endopeptidases / Q000096:biosynthesis*; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007376:Interleukin-2; D008565:Membrane Proteins; D013467:Sulindac; C025462:sulindac sulfide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D012697:Serine Endopeptidases; C467801:matriptase 2; D000068579:Celecoxib; C025463:sulindac sulfone; D015232:Dinoprostone