Differential Connexin Function Enhances Self-Renewal in Glioblastoma

作者：Hitomi Masahiro; Deleyrolle Loic P; Mulkearns Hubert Erin E; Jarrar Awad; Li Meizhang; Sinyuk Maksim; Otvos Balint; Brunet Sylvain; Flavahan William A; Hubert Christopher G; Goan Winston; Hale James S; Alvarado Alvaro G; Zhang Ao; Rohaus Mark; Oli Muna; Vedam Mai Vinata; Fortin Jeff M; Futch Hunter S; Griffith Benjamin; Wu Qiulian; Xia Chun hong; Gong Xiaohua; Ahluwalia Manmeet S; Rich Jeremy N; Reynolds Brent A^*; Lathia Justin D

来源：Cell Reports, 2015, 11(7): 1031-1042.

DOI：10.1016/j.celrep.2015.04.021

The coordination of complex tumor processes requires cells to rapidly modify their phenotype and is achieved by direct cell-cell communication through gap junction channels composed of connexins. Previous reports have suggested that gap junctions are tumor suppressive based on connexin 43 (Cx43), but this does not take into account differences in connexin-mediated ion selectivity and intercellular communication rate that drive gap junction diversity. We find that glioblastoma cancer stem cells (CSCs) possess functional gap junctions that can be targeted using clinically relevant compounds to reduce self-renewal and tumor growth. Our analysis reveals that CSCs express Cx46, while Cx43 is predominantly expressed in non-CSCs. During differentiation, Cx46 is reduced, while Cx43 is increased, and targeting Cx46 compromises CSC maintenance. The difference between Cx46 and Cx43 is reflected in elevated cell-cell communication and reduced resting membrane potential in CSCs. Our data demonstrate a pro-tumorigenic role for gap junctions that is dependent on connexin expression.

• 出版日期2015-5-19