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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 2013; 8(2):e57056Plos

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.

Authors+Show Affiliations

Cancer Program, Institute of Health and Biomedical Innovation and Faculty of Sciences and Technology, Queensland University of Technology, Kelvin Grove, Queensland, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23451143

Citation

Dong, Ying, et al. "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, vol. 8, no. 2, 2013, pp. e57056.
Dong Y, Stephens C, Walpole C, et al. 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. 2013;8(2):e57056.
Dong, Y., Stephens, C., Walpole, C., Swedberg, J. E., Boyle, G. M., Parsons, P. G., ... Clements, J. 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), pp. e57056. doi:10.1371/journal.pone.0057056.
Dong Y, et al. 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. 2013;8(2):e57056. PubMed PMID: 23451143.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paclitaxel resistance and multicellular spheroid formation are induced by kallikrein-related peptidase 4 in serous ovarian cancer cells in an ascites mimicking microenvironment. AU - Dong,Ying, AU - Stephens,Carson, AU - Walpole,Carina, AU - Swedberg,Joakim E, AU - Boyle,Glen M, AU - Parsons,Peter G, AU - McGuckin,Michael A, AU - Harris,Jonathan M, AU - Clements,Judith A, Y1 - 2013/02/25/ PY - 2012/08/30/received PY - 2013/01/16/accepted PY - 2013/3/2/entrez PY - 2013/3/2/pubmed PY - 2013/9/28/medline SP - e57056 EP - e57056 JF - PloS one JO - PLoS ONE VL - 8 IS - 2 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23451143/Paclitaxel_resistance_and_multicellular_spheroid_formation_are_induced_by_kallikrein_related_peptidase_4_in_serous_ovarian_cancer_cells_in_an_ascites_mimicking_microenvironment_ L2 - http://dx.plos.org/10.1371/journal.pone.0057056 DB - PRIME DP - Unbound Medicine ER -