Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Ibuprofen regulates the expression and function of membrane-associated serine proteases prostasin and matriptase

Authors: Andreas C. Chai, Andrew L. Robinson, Karl X. Chai, Li-Mei Chen

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

The glycosylphosphatidylinositol-anchored extracellular membrane serine protease prostasin is expressed in normal bladder urothelial cells. Bladder inflammation reduces prostasin expression and a loss of prostasin expression is associated with epithelial-mesenchymal transition (EMT) in human bladder transitional cell carcinomas. Non-steroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of various cancers including bladder cancer, but the molecular mechanisms underlying the anticancer effect of NSAIDs are not fully understood.

Methods

The normal human bladder urothelial cell line UROtsa, the normal human trophoblast cell line B6Tert-1, human bladder transitional cell carcinoma cell lines UM-UC-5 and UM-UC-9, and the human breast cancer cell line JIMT-1 were used for the study. Expression changes of the serine proteases prostasin and matriptase, and cyclooxygenases (COX-1 and COX-2) in these cells following ibuprofen treatments were analyzed by means of reverse-transcription/quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. The functional role of the ibuprofen-regulated prostasin in epithelial tight junction formation and maintenance was assessed by measuring the transepithelial electrical resistance (TEER) and epithelial permeability in the B6Tert-1 cells. Prostasin’s effects on tight junctions were also evaluated in B6Tert-1 cells over-expressing a recombinant human prostasin, silenced for prostasin expression, or treated with a functionally-blocking prostasin antibody. Matriptase zymogen activation was examined in cells over-expressing prostasin.

Results

Ibuprofen increased prostasin expression in the UROtsa and the B6Tert-1 cells. Cyclooxygenase-2 (COX-2) expression was up-regulated at both the mRNA and the protein levels in the UROtsa cells by ibuprofen in a dose-dependent manner, but was not a requisite for up-regulating prostasin expression. The ibuprofen-induced prostasin contributed to the formation and maintenance of the epithelial tight junctions in the B6Tert-1 cells. The matriptase zymogen was down-regulated in the UROtsa cells by ibuprofen possibly as a result of the increased prostasin expression because over-expressing prostasin leads to matriptase activation and zymogen down-regulation in the UROtsa, JIMT-1, and B6Tert-1 cells. The expression of prostasin and matriptase was differentially regulated by ibuprofen in the bladder cancer cells.

Conclusions

Ibuprofen has been suggested for use in treating bladder cancer. Our results bring the epithelial extracellular membrane serine proteases prostasin and matriptase into the potential molecular mechanisms of the anticancer effect of NSAIDs.
Literature
1.
Rawlings ND, Salvesen G. Handbood of Proteolytic Enzymes, Volume 3. Third Edition. ISBN: 978-0-12-382219-2, 2013.
2.
Chen LM, Chai KX. PRSS8 (protease, serine, 8). Atlas Genet Cytogenet Oncol Haematol. 2012;16(9):658–64.
3.
Yu JX, Chao L, Chao J. Prostasin is a novel human serine proteinase from seminal fluid. Purification, tissue distribution, and localization in prostate gland. J Biol Chem. 1994;269(29):18843–8.PubMed
4.
Yu JX, Chao L, Chao J. Molecular cloning, tissue-specific expression, and cellular localization of human prostasin mRNA. J Biol Chem. 1995;270(22):13483–9.PubMedCrossRef
5.
Yu JX, Chao L, Ward DC, Chao J. Structure and chromosomal localization of the human prostasin (PRSS8) gene. Genomics. 1996;32(3):334–40.PubMedCrossRef
6.
Chen LM, Hodge GB, Guarda LA, Welch JL, Greenberg NM, Chai KX. Down-regulation of prostasin serine protease: a potential invasion suppressor in prostate cancer. Prostate. 2001;48(2):93–103.PubMedCrossRef
7.
Chen LM, Chai KX. Prostasin serine protease inhibits breast cancer invasiveness and is transcriptionally regulated by promoter DNA methylation. Int J Cancer. 2002;97(3):323–9.PubMedCrossRef
8.
Takahashi S, Suzuki S, Inaguma S, Ikeda Y, Cho YM, Hayashi N, et al. Down-regulated expression of prostasin in high-grade or hormone-refractory human prostate cancers. Prostate. 2003;54(3):187–93.PubMedCrossRef
9.
Chen LM, Verity NJ, Chai KX. Loss of prostasin (PRSS8) in human bladder transitional cell carcinoma cell lines is associated with epithelial-mesenchymal transition (EMT). BMC Cancer. 2009;9:377.PubMedPubMedCentralCrossRef
10.
Mok SC, Chao J, Skates S, Wong K, Yiu GK, Muto MG, et al. Prostasin, a potential serum marker for ovarian cancer: identification through microarray technology. J Natl Cancer Inst. 2001;93(19):1458–64.PubMedCrossRef
11.
Chen LM, Zhang X, Chai KX. Regulation of prostasin expression and function in the prostate. Prostate. 2004;59(1):1–12.PubMedCrossRef
12.
Narikiyo T, Kitamura K, Adachi M, Miyoshi T, Iwashita K, Shiraishi N, et al. Regulation of prostasin by aldosterone in the kidney. J Clin Invest. 2002;109(3):401–8.PubMedPubMedCentralCrossRef
13.
Tuyen DG, Kitamura K, Adachi M, Miyoshi T, Wakida N, Nagano J, et al. Inhibition of prostasin expression by TGF-beta1 in renal epithelial cells. Kidney Int. 2005;67(1):193–200.PubMedCrossRef
14.
Chen M, Chen LM, Chai KX. Androgen regulation of prostasin gene expression is mediated by sterol-regulatory element-binding proteins and SLUG. Prostate. 2006;66(9):911–20.PubMedCrossRef
15.
Chen M, Chen LM, Chai KX. Mechanisms of sterol regulatory element-binding protein-2 (SREBP-2) regulation of human prostasin gene expression. Biochem Biophys Res Commun. 2006;346(4):1245–53.PubMedCrossRef
16.
Chen LM, Wang C, Chen M, Marcello MR, Chao J, Chao L, et al. Prostasin attenuates inducible nitric oxide synthase expression in lipopolysaccharide-induced urinary bladder inflammation. Am J Physiol Renal Physiol. 2006;291(3):F567–77.PubMedCrossRef
17.
Chen M, Fu YY, Lin CY, Chen LM, Chai KX. Prostasin induces protease-dependent and independent molecular changes in the human prostate carcinoma cell line PC-3. Biochim Biophys Acta. 2007;1773(7):1133–40.PubMedPubMedCentralCrossRef
18.
Chen LM, Hatfield ML, Fu YY, Chai KX. Prostasin regulates iNOS and cyclin D1 expression by modulating protease-activated receptor-2 signaling in prostate epithelial cells. Prostate. 2009;69(16):1790–801.PubMedCrossRef
19.
Camerer E, Barker A, Duong DN, Ganesan R, Kataoka H, Cornelissen I, et al. Local protease signaling contributes to neural tube closure in the mouse embryo. Dev Cell. 2010;18(1):25–38.PubMedPubMedCentralCrossRef
20.
Netzel-Arnett S, Currie BM, Szabo R, Lin CY, Chen LM, Chai KX, et al. Evidence for a matriptase-prostasin proteolytic cascade regulating terminal epidermal differentiation. J Biol Chem. 2006;281(44):32941–5.PubMedCrossRef
21.
Fan B, Wu TD, Li W, Kirchhofer D. Identification of hepatocyte growth factor activator inhibitor-1B as a potential physiological inhibitor of prostasin. J Biol Chem. 2005;280(41):34513–20.PubMedCrossRef
22.
Szabo R, Uzzun Sales K, Kosa P, Shylo NA, Godiksen S, Hansen KK, et al. Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation. PLoS Genet. 2012;8(8).
23.
Leyvraz C, Charles RP, Rubera I, Guitard M, Rotman S, Breiden B, et al. The epidermal barrier function is dependent on the serine protease CAP1/Prss8. J Cell Biol. 2005;170(3):487–96.PubMedPubMedCentralCrossRef
24.
Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123(6 Pt 2):1777–88.PubMedCrossRef
25.
Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and −2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 1998;141(7):1539–50.PubMedPubMedCentralCrossRef
26.
Guo S, Nighot M, Al-Sadi R, Alhmoud T, Nighot P, Ma TY. Lipopolysaccharide regulation of intestinal tight junction permeability is mediated by tlr4 signal transduction pathway activation of FAK and MyD88. J Immunol. 2015;195(10):4999–5010.PubMedCrossRef
27.
Uchimura K, Hayata M, Mizumoto T, Miyasato Y, Kakizoe Y, Morinaga J, et al. The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signaling. Nat Commun. 2014;5:3428.PubMedPubMedCentralCrossRef
28.
Harris RE, Beebe-Donk J, Doss H, Burr Doss D. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncol Rep. 2005;13(4):559–83.PubMed
29.
Khwaja F, Allen J, Lynch J, Andrews P, Djakiew D. Ibuprofen inhibits survival of bladder cancer cells by induced expression of the p75NTR tumor suppressor protein. Cancer Res. 2004;64(17):6207–13.PubMedCrossRef
30.
Fu YY, Gao WL, Chen M, Chai KX, Wang YL, Chen LM. Prostasin regulates human placental trophoblast cell proliferation via the epidermal growth factor receptor signaling pathway. Hum Reprod. 2010;25(3):623–32.PubMedCrossRef
31.
Chen LM, Skinner ML, Kauffman SW, Chao J, Chao L, Thaler CD, et al. Prostasin is a glycosylphosphatidylinositol-anchored active serine protease. J Biol Chem. 2001;276(24):21434–42.PubMedCrossRef
32.
Buzza MS, Martin EW, Driesbaugh KH, Désilets A, Leduc R, Antalis TM. Prostasin is required for matriptase activation in intestinal epithelial cells to regulate closure of the paracellular pathway. J Biol Chem. 2013;288(15):10328–37.PubMedPubMedCentralCrossRef
33.
Frateschi S, Camerer E, Crisante G, Rieser S, Membrez M, Charles RP, et al. PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin. Nat Commun. 2011;2:161.PubMedPubMedCentralCrossRef
34.
Stein J, Volk HD, Liebenthal C, Krüger DH, Prösch S. Tumour necrosis factor alpha stimulates the activity of the human cytomegalovirus major immediate early enhancer/promoter in immature monocytic cells. J Gen Virol. 1993;74(Pt 11):2333–8.PubMedCrossRef
35.
Lee MS, Tseng IC, Wang Y, Kiyomiya K, Johnson MD, Dickson RB, et al. Autoactivation of matriptase in vitro: requirement for biomembrane and LDL receptor domain. Am J Physiol Cell Physiol. 2007;293(1):C95–C105.PubMedCrossRef
36.
Shimomura T1, Denda K, Kitamura A, Kawaguchi T, Kito M, Kondo J, et al. Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor. J Biol Chem. 1997;272(10):6370–6.PubMedCrossRef
37.
Lichtenberger LM, Zhou Y, Jayaraman V, Doyen JR, O’Neil RG, Dial EJ, et al. Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine. Biochim Biophys Acta. 2012;1821(7):994–1002.PubMedPubMedCentralCrossRef
38.
Hummler E, Dousse A, Rieder A, Stehle JC, Rubera I, Osterheld MC, et al. The channel-activating protease CAP1/Prss8 is required for placental labyrinth maturation. PLoS One. 2013;8(2):e55796.PubMedPubMedCentralCrossRef
39.
Szabo R, Peters DE, Kosa P, Camerer E, Bugge TH. Regulation of feto-maternal barrier by matriptase- and PAR-2-mediated signaling is required for placental morphogenesis and mouse embryonic survival. PLoS Genet. 2014;10(7):e1004470.PubMedPubMedCentralCrossRef
40.
Yang Y, Zhang J, Gong Y, Liu X, Bai Y, Xu W, et al. Increased expression of prostasin contributes to early-onset severe preeclampsia through inhibiting trophoblast invasion. J Perinatol. 2015;35(1):16–22.PubMedCrossRef
41.
Sun Y, Rowehl LM, Huang L, Mackenzie GG, Vrankova K, Komninou D, et al. Phospho-ibuprofen (MDC-917) suppresses breast cancer growth: an effect controlled by the thioredoxin system. Breast Cancer Res. 2012;14(1):R20.PubMedPubMedCentralCrossRef
Metadata
Title
Ibuprofen regulates the expression and function of membrane-associated serine proteases prostasin and matriptase
Authors
Andreas C. Chai
Andrew L. Robinson
Karl X. Chai
Li-Mei Chen
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-2039-6

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

Lack of significant association between serum inflammatory cytokine profiles and the presence of colorectal adenoma

Research article

Adenosine A2b receptor promotes progression of human oral cancer

Study protocol

TOPGEAR: a randomised phase III trial of perioperative ECF chemotherapy versus preoperative chemoradiation plus perioperative ECF chemotherapy for resectable gastric cancer (an international, intergroup trial of the AGITG/TROG/EORTC/NCIC CTG)

Research article

Constitutive expression of AhR and BRCA-1 promoter CpG hypermethylation as biomarkers of ERα-negative breast tumorigenesis

Study protocol

Multiparametric MRI as an outcome predictor for anal canal cancer managed with chemoradiotherapy

Research article

A mutation screening of oncogenes, tumor suppressor gene TP53 and nuclear encoded mitochondrial complex I genes in oncocytic thyroid tumors
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits