Development of a Cx46 Targeting Strategy for Cancer Stem Cells

Publication date: 23 April 2019Source: Cell Reports, Volume 27, Issue 4Author(s): Erin E. Mulkearns-Hubert, Luke A. Torre-Healy, Daniel J. Silver, Jennifer T. Eurich, Defne Bayik, Emily Serbinowski, Masahiro Hitomi, John Zhou, Bartlomiej Przychodzen, Renliang Zhang, Samuel A. Sprowls, James S. Hale, Tyler J. Alban, Artem Berezovsky, Brent A. Bell, Paul R. Lockman, Babal K. Jha, Justin D. LathiaSummaryGap-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 communica...
Source: Cell Reports - Category: Cytology Source Type: research