Connexin 43 confers chemoresistance through activating PI3K

Circumventing chemoresistance is crucial for effectively treating cancer including glioblastoma, a lethal brain cancer. The gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to chemotherapy; however, targeting Cx43 is difficult because mechanisms underlying Cx43-mediated chemoresistance remain elusive. Here we report that Cx43, but not other connexins, is highly expressed in a subpopulation of glioblastoma and Cx43 mRNA levels strongly correlate with poor prognosis and chemoresistance in this population, making Cx43 the prime therapeutic target among all connexins. Depleting Cx43 or treating cells with alpha CT1-a Cx43 peptide inhibitor that sensitizes glioblastoma to the chemotherapy temozolomide-inactivates phosphatidylinositol-3 kinase (PI3K), whereas overexpression of Cx43 activates this signaling. Moreover, alpha CT1-induced chemo-sensitization is counteracted by a PI3K active mutant. Further research reveals that alpha CT1 inactivates PI3K without blocking the release of PI3K-activating molecules from membrane channels and that Cx43 selectively binds to the PI3K catalytic subunit beta (PIK3CB, also called PI3K beta or p110 beta), suggesting that Cx43 activates PIK3CB/p110 beta independent of its channel functions. To explore the therapeutic potential of simultaneously targeting Cx43 and PIK3CB/p110 beta, alpha CT1 is combined with TGX-221 or GSK2636771, two PIK3CB/p110 beta-selective inhibitors. These two different treatments synergistically inactivate PI3K and sensitize glioblastoma cells to temozolomide in vitro and in vivo. Our study has revealed novel mechanistic insights into Cx43/PI3K-mediated temozolomide resistance in glioblastoma and demonstrated that targeting Cx43 and PIK3CB/p110 beta together is an effective therapeutic approach for overcoming chemoresistance.

Automated summary

This study reveals that the protein connexin 43 (Cx43) is highly expressed in a subpopulation of glioblastoma and is associated with poor prognosis and chemoresistance. Targeting Cx43 can sensitize glioblastoma cells to chemotherapy by inactivating phosphatidylinositol-3 kinase (PI3K). Furthermore, combining Cx43 inhibition with PIK3CB/p110 beta-selective inhibitors can synergistically overcome chemoresistance in glioblastoma cells.