Author ORCID Identifier
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https://orcid.org/0000-0003-1995-0586
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https://orcid.org/0000-0002-3261-140X
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https://orcid.org/0000-0002-6995-9944
https://orcid.org/0000-0002-7660-5255
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Document Type
Article
Publication Date
2019
College/Unit
School of Pharmacy
Department/Program/Center
Pharmaceutical Sciences
Abstract
Gap-junction-mediated cell-cell communication enables tumor cells to synchronize complex processes. We previously found that glioblastoma cancer stem cells (CSCs) express higher levels of the gap junction protein Cx46 compared to non-stem tumor cells (non-CSCs) and that this was necessary and sufficient for CSC maintenance. To understand the mechanism underlying this requirement, we use point mutants to disrupt specific functions of Cx46 and find that Cx46-mediated gap-junction coupling is critical for CSCs. To develop a Cx46 targeting strategy, we screen a clinically relevant small molecule library and identify clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuates proliferation, self-renewal, and tumor growth and synergizes with temozolomide to induce apoptosis. Although clofazimine does not cross the blood-brain barrier, the combination of clofazimine derivatives optimized for brain penetrance 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.
Digital Commons Citation
Mulkeans-Hubert, Erin E.; Torre-Healy, Luke A.; Silver, Daniel J,; Eurich, Jennifer T.; Bayik, Defne; Serbinowski, Emily; Hitomi, Masahiro; Zhou, John; Przychodzen, Bartlomiej; Zhang, Renliang; Sprowls, Samuel A.; Hale, James S.; Alban, Tyler J.; Berezovsky, Artem; Bell, Brent A.; Lockman, Paul R.; Jha, Babal K.; and Lathia, Justin D., "Development of a Cx46 Targeting Strategy for Cancer Stem Cells" (2019). Faculty & Staff Scholarship. 2140.
https://researchrepository.wvu.edu/faculty_publications/2140
Source Citation
Mulkearns-Hubert, E. E., Torre-Healy, L. A., Silver, D. J., Eurich, J. T., Bayik, D., Serbinowski, E., … Lathia, J. D. (2019). Development of a Cx46 Targeting Strategy for Cancer Stem Cells. Cell Reports, 27(4), 1062–1072.e5. https://doi.org/10.1016/j.celrep.2019.03.079
Comments
1062 Cell Reports 27, 1062–1072, April 23, 2019 ª 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).