Paclitaxel resistance and multicellular spheroid formation are induced by kallikrein-related peptidase 4 in serous ovarian cancer cells in an ascites mimicking microenvironment

Dong, Ying, Stephens, Carson, Walpole, Carina, Swedberg, Joakim E., Boyle, Glen M., Parsons, Peter G., McGuckin, Michael A., Harris, Jonathan M. and Clements, Judith A. (2013) Paclitaxel resistance and multicellular spheroid formation are induced by kallikrein-related peptidase 4 in serous ovarian cancer cells in an ascites mimicking microenvironment. PLoS One, 8 2: e57056.1-e57056.12. doi:10.1371/journal.pone.0057056

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Author Dong, Ying
Stephens, Carson
Walpole, Carina
Swedberg, Joakim E.
Boyle, Glen M.
Parsons, Peter G.
McGuckin, Michael A.
Harris, Jonathan M.
Clements, Judith A.
Title Paclitaxel resistance and multicellular spheroid formation are induced by kallikrein-related peptidase 4 in serous ovarian cancer cells in an ascites mimicking microenvironment
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-02-25
Sub-type Article (original research)
DOI 10.1371/journal.pone.0057056
Open Access Status DOI
Volume 8
Issue 2
Start page e57056.1
End page e57056.12
Total pages 12
Editor Georgia Sotiropoulou
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2014
Language eng
Formatted abstract
High tumor kallikrein-related-peptidase 4 (KLK4) levels are associated with a poor outcome for women with serous epithelial ovarian cancer (EOC), for which peritoneal dissemination and chemoresistance are key events. To determine the role of KLK4 in these events, we examined KLK4-transfected SKOV-3 and endogenous KLK4 expressing OVCA432 cells in 3-dimensional (3D) suspension culture to mimic the ascites microenvironment. KLK4-SKOV-3 cells formed multicellular aggregates (MCAs) as seen in ascites, as did SKOV-3 cells treated with active KLK4. MCA formation was reduced by treatment with a KLK4 blocking antibody or the selective active site KLK4 sunflower trypsin inhibitor (SFTI-FCQR). KLK4-MCAs formed larger cancer cell foci in mesothelial cell monolayers than those formed by vector and native SKOV-3 cells, suggesting KLK4-MCAs are highly invasive in the peritoneal microenvironment. A high level of KLK4 is expressed by ascitic EOC cells compared to matched primary tumor cells, further supporting its role in the ascitic microenvironment. Interestingly, KLK4 transfected SKOV-3 cells expressed high levels of the KLK4 substrate, urokinase plasminogen activator (uPA), particularly in 3D-suspension, and high levels of both KLK4 and uPA were observed in patient cells taken from ascites. Importantly, the KLK4-MCAs were paclitaxel resistant which was reversed by SFTI-FCQR and to a lesser degree by the general serine protease inhibitor, Aprotinin, suggesting that in addition to uPA, other as yet unidentified substrates of KLK4 must be involved. Nonetheless, these data suggest that KLK4 inhibition, in conjunction with paclitaxel, may improve the outcome for women with serous epithelial ovarian cancer and high KLK4 levels in their tumors.
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Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
School of Medicine Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 18 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 14 Jan 2014, 16:04:45 EST by Michael Mcguckin on behalf of School of Biomedical Sciences