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Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance.
Gynecol Oncol 2012; 127(3):569-78GO

Abstract

OBJECTIVE

Chemoresistance is a critical feature of advanced ovarian cancer with only 30% of patients surviving longer than 5 years. We have previously shown that four kallikrein-related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4-7), are implicated in peritoneal invasion and tumour growth, but underlying mechanisms were not identified. We also reported that KLK7 overexpression confers chemoresistance to paclitaxel, and cell survival via integrins. In this study, we further explored the functional consequenses of overexpression of all four KLKs (KLK4-7) simultaneously in the ovarian cancer cell line, OV-MZ-6, and its impact on integrin expression and signalling, cell adhesion and survival as contributors to chemoresistance and metastatic progression.

METHODS

Quantitative gene and protein expression analyses, confocal microscopy, cell adhesion and chemosensitivity assays were performed.

RESULTS

Expression of α5β1/αvβ3 integrins was downregulated upon combined stable KLK4-7 overexpression in OV-MZ-6 cells. Accordingly, the adhesion of these cells to vitronectin and fibronectin, the extracellular matrix binding proteins of α5β1/αvβ3 integrins and two predominant proteins of the peritoneal matrix, was decreased. KLK4-7-transfected cells were more resistant to paclitaxel (10-100 nmol/L: 38-54%), but not to carboplatin, which was associated with decreased apoptotic stimuli. However, the KLK4-7-induced paclitaxel resistance was not blocked by the MEK1/2 inhibitor, U0126.

CONCLUSIONS

This study demonstrates that combined KLK4-7 expression by ovarian cancer cells promotes reduced integrin expression with consequently less cell-matrix attachment, and insensitivity to paclitaxel mediated by complex integrin and MAPK independent interactions, indicative of a malignant phenotype and disease progression suggesting a role for these KLKs in this process.

Authors+Show Affiliations

Cancer Program, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, Queensland 4059, Australia.No 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

22964375

Citation

Loessner, Daniela, et al. "Combined Expression of KLK4, KLK5, KLK6, and KLK7 By Ovarian Cancer Cells Leads to Decreased Adhesion and Paclitaxel-induced Chemoresistance." Gynecologic Oncology, vol. 127, no. 3, 2012, pp. 569-78.
Loessner D, Quent VM, Kraemer J, et al. Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance. Gynecol Oncol. 2012;127(3):569-78.
Loessner, D., Quent, V. M., Kraemer, J., Weber, E. C., Hutmacher, D. W., Magdolen, V., & Clements, J. A. (2012). Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance. Gynecologic Oncology, 127(3), pp. 569-78. doi:10.1016/j.ygyno.2012.09.001.
Loessner D, et al. Combined Expression of KLK4, KLK5, KLK6, and KLK7 By Ovarian Cancer Cells Leads to Decreased Adhesion and Paclitaxel-induced Chemoresistance. Gynecol Oncol. 2012;127(3):569-78. PubMed PMID: 22964375.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance. AU - Loessner,Daniela, AU - Quent,Verena M C, AU - Kraemer,Julia, AU - Weber,Eva C, AU - Hutmacher,Dietmar W, AU - Magdolen,Viktor, AU - Clements,Judith A, Y1 - 2012/09/08/ PY - 2012/05/11/received PY - 2012/08/10/revised PY - 2012/09/02/accepted PY - 2012/9/12/entrez PY - 2012/9/12/pubmed PY - 2013/2/26/medline SP - 569 EP - 78 JF - Gynecologic oncology JO - Gynecol. Oncol. VL - 127 IS - 3 N2 - OBJECTIVE: Chemoresistance is a critical feature of advanced ovarian cancer with only 30% of patients surviving longer than 5 years. We have previously shown that four kallikrein-related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4-7), are implicated in peritoneal invasion and tumour growth, but underlying mechanisms were not identified. We also reported that KLK7 overexpression confers chemoresistance to paclitaxel, and cell survival via integrins. In this study, we further explored the functional consequenses of overexpression of all four KLKs (KLK4-7) simultaneously in the ovarian cancer cell line, OV-MZ-6, and its impact on integrin expression and signalling, cell adhesion and survival as contributors to chemoresistance and metastatic progression. METHODS: Quantitative gene and protein expression analyses, confocal microscopy, cell adhesion and chemosensitivity assays were performed. RESULTS: Expression of α5β1/αvβ3 integrins was downregulated upon combined stable KLK4-7 overexpression in OV-MZ-6 cells. Accordingly, the adhesion of these cells to vitronectin and fibronectin, the extracellular matrix binding proteins of α5β1/αvβ3 integrins and two predominant proteins of the peritoneal matrix, was decreased. KLK4-7-transfected cells were more resistant to paclitaxel (10-100 nmol/L: 38-54%), but not to carboplatin, which was associated with decreased apoptotic stimuli. However, the KLK4-7-induced paclitaxel resistance was not blocked by the MEK1/2 inhibitor, U0126. CONCLUSIONS: This study demonstrates that combined KLK4-7 expression by ovarian cancer cells promotes reduced integrin expression with consequently less cell-matrix attachment, and insensitivity to paclitaxel mediated by complex integrin and MAPK independent interactions, indicative of a malignant phenotype and disease progression suggesting a role for these KLKs in this process. SN - 1095-6859 UR - https://www.unboundmedicine.com/medline/citation/22964375/Combined_expression_of_KLK4_KLK5_KLK6_and_KLK7_by_ovarian_cancer_cells_leads_to_decreased_adhesion_and_paclitaxel_induced_chemoresistance_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0090-8258(12)00734-2 DB - PRIME DP - Unbound Medicine ER -