Inhibition of cyclooxygenase-2-mediated matriptase activation contributes to the suppression of prostate cancer cell motility and metastasis
Journal
Oncogene
Journal Volume
36
Journal Issue
32
Pages
4597-4609
Date Issued
2017
Author(s)
Lan S.-W.
Cheng T.-S.
Lai P.-F.
Tsai C.-H.
Hsu T.-W.
Lin H.-Y.
Shyu H.-Y.
Wu S.-R.
Lin H.-H.
Hsiao P.-W.
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 E 2 (PGE 2) 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.
SDGs
Other Subjects
acetylsalicylic acid; celecoxib; cyclooxygenase 2; etoricoxib; ibuprofen; interleukin 1beta; matriptase; prostaglandin E2; sulindac sulfide; sulindac sulfone; celecoxib; cyclooxygenase 2; cyclooxygenase 2 inhibitor; interleukin 2; matriptase 2; membrane protein; prostaglandin E2; PTGS2 protein, human; serine proteinase; sulindac; sulindac sulfide; sulindac sulfone; animal experiment; animal model; animal tissue; Article; cancer inhibition; cancer patient; carcinogenesis; cell invasion; cell motility; cell viability; controlled study; drug targeting; enzyme activation; enzyme inhibition; gene silencing; human; human tissue; IC50; lung metastasis; male; metastasis; mouse; nonhuman; priority journal; prostate cancer; prostate cancer cell line; protein expression; protein function; signal transduction; tumor xenograft; upregulation; analogs and derivatives; animal; biosynthesis; cell motion; drug effects; drug screening; enzymology; HEK293 cell line; inflammation; metabolism; metastasis; pathology; Prostatic Neoplasms; SCID mouse; tumor cell culture; tumor invasion; Animals; Celecoxib; Cell Movement; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; HEK293 Cells; Humans; Inflammation; Interleukin-2; Male; Membrane Proteins; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Prostatic Neoplasms; Serine Endopeptidases; Sulindac; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
Publisher
Nature Publishing Group
Type
journal article