Circumventing chemoresistance is crucial for effectively treating glioblastoma due to limited therapeutic options. The gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to the frontline chemotherapy temozolomide; however, targeting Cx43 is difficult because mechanisms underlying Cx43-mediated chemoresistance remain elusive. Here we show that Cx43, but not other connexins, is highly expressed in glioblastoma and strongly correlates with poor patient prognosis and chemoresistance, making Cx43 the prime therapeutic target among all connexins. The intracellular carboxyl terminus of Cx43 binds to phosphatidylinositol 3-kinase (PI3K) catalytic subunit beta (PIK3CB, also called PI3Kbeta or p110beta), thereby activating PI3K signaling independent of Cx43-channels and subsequently inducing temozolomide resistance. A combination of alphaCT1, a Cx43-targeting peptide inhibitor, and PIK3CB-selective inhibitors restores temozolomide sensitivity in vitro and in vivo. This study not only reveals novel mechanistic insights into chemoresistance in glioblastoma, but also demonstrates that targeting Cx43 and PIK3CB/p110beta is an effective approach for overcoming chemoresistance.

中文翻译：

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连接蛋白43通过激活PI3K赋予化学抗性

由于有限的治疗选择，规避化学耐药性对于有效治疗胶质母细胞瘤至关重要。间隙连接蛋白连接蛋白43（Cx43）使胶质母细胞瘤对一线化疗替莫唑胺具有耐药性。但是，靶向Cx43是困难的，因为Cx43介导的化学抗性的潜在机制尚不清楚。在这里，我们显示Cx43在成胶质母细胞瘤中高表达，但与其他连接蛋白无关，并且与不良的患者预后和化学抗性密切相关，使Cx43成为所有连接蛋白中的主要治疗靶标。Cx43的细胞内羧基末端与磷脂酰肌醇3-激酶（PI3K）催化亚基beta（PIK3CB，也称为PI3Kbeta或p110beta）结合，从而激活独立于Cx43通道的PI3K信号传导，并随后诱导替莫唑胺抗性。alphaCT1，一种靶向Cx43的肽抑制剂和PIK3CB选择性抑制剂的组合可在体内和体外恢复替莫唑胺的敏感性。这项研究不仅揭示了胶质母细胞瘤化学抗药性的新颖机制，而且表明靶向Cx43和PIK3CB / p110beta是克服化学抗药性的有效方法。