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Molecular Cancer Research
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Cell Fate Decisions

Ovarian Tumor Cell Expression of Claudin-4 Reduces Apoptotic Response to Paclitaxel

Christopher Breed, Douglas A. Hicks, Patricia G. Webb, Carly E. Galimanis, Benjamin G. Bitler, Kian Behbakht and Heidi K. Baumgartner
Christopher Breed
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
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Douglas A. Hicks
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
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Patricia G. Webb
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
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Carly E. Galimanis
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
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Benjamin G. Bitler
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
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Kian Behbakht
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
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Heidi K. Baumgartner
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
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  • For correspondence: Heidi.Wilson@ucdenver.edu
DOI: 10.1158/1541-7786.MCR-18-0451 Published March 2019
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Abstract

A significant factor contributing to poor survival rates for patients with ovarian cancer is the insensitivity of tumors to standard-of-care chemotherapy. In this study, we investigated the effect of claudin-4 expression on ovarian tumor cell apoptotic response to cisplatin and paclitaxel. We manipulated claudin-4 gene expression by silencing expression [short hairpin RNA (shRNA)] in cells with endogenously expressed claudin-4 or overexpressing claudin-4 in cells that natively do not express claudin-4. In addition, we inhibited claudin-4 activity with a claudin mimic peptide (CMP). We monitored apoptotic response by caspase-3 and Annexin V binding. We examined proliferation rate by counting the cell number over time as well as measuring the number of mitotic cells. Proximity ligation assays, immunoprecipitation (IP), and immunofluorescence were performed to examine interactions of claudin-4. Western blot analysis of tubulin in cell fractions was used to determine the changes in tubulin polymerization with changes in claudin-4 expression. Results show that claudin-4 expression reduced epithelial ovarian cancer (EOC) cell apoptotic response to paclitaxel. EOCs without claudin-4 proliferated more slowly with enhanced mitotic arrest compared with the cells expressing claudin-4. Furthermore, our results indicate that claudin-4 interacts with tubulin, having a profound effect on the structure and polymerization of the microtubule network. In conclusion, we demonstrate that claudin-4 reduces the ovarian tumor cell response to microtubule-targeting paclitaxel and disrupting claudin-4 with CMP can restore apoptotic response.

Implications: These results suggest that claudin-4 expression may provide a biomarker for paclitaxel response and can be a target for new therapeutic strategies to improve response.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received May 3, 2018.
  • Revision received October 11, 2018.
  • Accepted December 20, 2018.
  • Published first January 3, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Research: 17 (3)
March 2019
Volume 17, Issue 3
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Ovarian Tumor Cell Expression of Claudin-4 Reduces Apoptotic Response to Paclitaxel
Christopher Breed, Douglas A. Hicks, Patricia G. Webb, Carly E. Galimanis, Benjamin G. Bitler, Kian Behbakht and Heidi K. Baumgartner
Mol Cancer Res March 1 2019 (17) (3) 741-750; DOI: 10.1158/1541-7786.MCR-18-0451

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Ovarian Tumor Cell Expression of Claudin-4 Reduces Apoptotic Response to Paclitaxel
Christopher Breed, Douglas A. Hicks, Patricia G. Webb, Carly E. Galimanis, Benjamin G. Bitler, Kian Behbakht and Heidi K. Baumgartner
Mol Cancer Res March 1 2019 (17) (3) 741-750; DOI: 10.1158/1541-7786.MCR-18-0451
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Molecular Cancer Research
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