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Development of a Cx46 Targeting Strategy for Cancer Stem Cells

46 Pages Posted: 7 Jun 2018 Sneak Peek Status: Published

See all articles by Erin E. Mulkearns-Hubert

Erin E. Mulkearns-Hubert

Cleveland Clinic - Cellular and Molecular Medicine

Luke A. Torre-Healy

Cleveland Clinic - Cellular and Molecular Medicine

Daniel J. Silver

Cleveland Clinic - Department of Molecular Medicine

Jennifer T. Eurich

Cleveland Clinic - Cellular and Molecular Medicine

Emily Serbinowski

Cleveland Clinic - Cellular and Molecular Medicine

Masahiro Hitomi

Cleveland Clinic - Cellular and Molecular Medicine; Cleveland Clinic - Department of Molecular Medicine

John Zhou

Cleveland Clinic - Cellular and Molecular Medicine; Cleveland Clinic - Department of Molecular Medicine

Bartlomiej Przychodzen

Cleveland Clinic - Translational Hematology & Oncology

Renliang Zhang

Cleveland Clinic - Proteomics and Metabolomics Core

Samuel A. Sprowls

West Virginia University - Department of Pharmaceutical Sciences

James S. Hale

Cleveland Clinic - Cellular and Molecular Medicine

Tyler Alban

Cleveland Clinic - Cellular and Molecular Medicine; Cleveland Clinic - Department of Molecular Medicine

Artem Berezovsky

Cleveland Clinic - Cellular and Molecular Medicine

Brent A. Bell

Cleveland Clinic - Cole Eye Institute

Paul R. Lockman

West Virginia University - Department of Pharmaceutical Sciences

Babal K. Jha

Cleveland Clinic - Department of Molecular Medicine; Cleveland Clinic - Translational Hematology & Oncology; Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center

Justin D. Lathia

Cleveland Clinic - Cellular and Molecular Medicine; Cleveland Clinic - Department of Molecular Medicine; Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center

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Abstract

Gap junction-mediated cell-cell communication enables tumor cells to synchronize the execution of complex processes. Despite the connexin family of gap junction proteins being considered tumor suppressors, we previously found that glioblastoma cancer stem cells (CSCs) express higher levels of Cx46 compared to non-stem tumor cells, and this was necessary and sufficient for CSC maintenance. To develop a Cx46 targeting strategy, we utilized point mutants to disrupt specific functions of Cx46 and found that gap junction coupling was the critical function of Cx46 for CSCs. Based on this finding, we screened a clinically relevant library of small molecules and identified clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuated proliferation, self-renewal, and tumor growth and synergized with temozolomide to induce apoptosis. These data suggest that combining clofazimine with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy.

Keywords: Glioblastoma, Cancer Stem Cells, Connexin, Gap Junction, Drug Repurposing

Suggested Citation

Mulkearns-Hubert, Erin E. and Torre-Healy, Luke A. and Silver, Daniel J. and Eurich, Jennifer T. and Serbinowski, Emily and Hitomi, Masahiro and Zhou, John and Przychodzen, Bartlomiej and Zhang, Renliang and Sprowls, Samuel A. and Hale, James S. and Alban, Tyler and Berezovsky, Artem and Bell, Brent A. and Lockman, Paul R. and Jha, Babal K. and Lathia, Justin D., Development of a Cx46 Targeting Strategy for Cancer Stem Cells (2018). Available at SSRN: https://ssrn.com/abstract=3188436 or http://dx.doi.org/10.2139/ssrn.3188436
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Erin E. Mulkearns-Hubert (Contact Author)

Cleveland Clinic - Cellular and Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Luke A. Torre-Healy

Cleveland Clinic - Cellular and Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Daniel J. Silver

Cleveland Clinic - Department of Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Jennifer T. Eurich

Cleveland Clinic - Cellular and Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Emily Serbinowski

Cleveland Clinic - Cellular and Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Masahiro Hitomi

Cleveland Clinic - Cellular and Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Cleveland Clinic - Department of Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

John Zhou

Cleveland Clinic - Cellular and Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Cleveland Clinic - Department of Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Bartlomiej Przychodzen

Cleveland Clinic - Translational Hematology & Oncology

9500 Euclid Avenue
Cleveland, OH 44195
United States

Renliang Zhang

Cleveland Clinic - Proteomics and Metabolomics Core

Cleveland, OH 44195
United States

Samuel A. Sprowls

West Virginia University - Department of Pharmaceutical Sciences

Morgantown, WV
United States

James S. Hale

Cleveland Clinic - Cellular and Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Tyler Alban

Cleveland Clinic - Cellular and Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Cleveland Clinic - Department of Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Artem Berezovsky

Cleveland Clinic - Cellular and Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Brent A. Bell

Cleveland Clinic - Cole Eye Institute

Cleveland, OH 44195
United States

Paul R. Lockman

West Virginia University - Department of Pharmaceutical Sciences

Morgantown, WV
United States

Babal K. Jha

Cleveland Clinic - Department of Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Cleveland Clinic - Translational Hematology & Oncology

9500 Euclid Avenue
Cleveland, OH 44195
United States

Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center

Cleveland, OH 44195
United States

Justin D. Lathia

Cleveland Clinic - Cellular and Molecular Medicine ( email )

9500 Euclid Avenue
Cleveland, OH 44195
United States

Cleveland Clinic - Department of Molecular Medicine ( email )

9500 Euclid Avenue
Cleveland, OH 44195
United States

Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center ( email )

Cleveland, OH 44195
United States

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