Smyth James W, Guo Sujuan, Chaunsali Lata, O'Rourke Laurie, Dahlka Jacob, Deaver Stacie, Lunski Michael, Nurmemmedov Elmar, Sontheimer Harald, Sheng Zhi, Gourdie Robert G, Lamouille Samy
Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, VA, 24016, USA.
Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA.
Cell Death Dis. 2025 May 16;16(1):388. doi: 10.1038/s41419-025-07514-2.
Glioblastoma (GBM) is the most common primary tumor of the central nervous system. One major challenge in GBM treatment is the resistance to chemotherapy and radiotherapy observed in subpopulations of cancer cells, including GBM stem-like cells (GSCs). These cells have the capacity to self-renew and differentiate and as such, GSCs participate in tumor recurrence following treatment. The gap junction protein connexin43 (Cx43) has complex roles in oncogenesis and we have previously demonstrated an association between Cx43 and GBM chemotherapy resistance. Here, we report, for the first time, increased direct interaction between non-junctional Cx43 and microtubules in the cytoplasm of GSCs. We hypothesize that non-junctional Cx43/microtubule complexing is critical for GSC maintenance and survival and sought to specifically disrupt this interaction while maintaining other Cx43 functions, such as gap junction formation. Using a Cx43 mimetic peptide of the carboxyl terminal tubulin-binding domain of Cx43 (JM2), we successfully disrupted Cx43 interaction with microtubules in GSCs. Importantly, administration of JM2 significantly decreased GSC survival in vitro, and limited GSC-derived and GBM patient-derived xenograft tumor growth in vivo. Together, these results identify JM2 as a novel peptide drug to ablate GSCs in GBM treatment.
胶质母细胞瘤（GBM）是中枢神经系统最常见的原发性肿瘤。GBM治疗中的一个主要挑战是在包括GBM干细胞样细胞（GSCs）在内的癌细胞亚群中观察到的对化疗和放疗的抗性。这些细胞具有自我更新和分化的能力，因此，GSCs参与治疗后的肿瘤复发。间隙连接蛋白连接蛋白43（Cx43）在肿瘤发生中具有复杂的作用，我们之前已经证明Cx43与GBM化疗抗性之间存在关联。在这里，我们首次报道了GSCs细胞质中非连接性Cx43与微管之间直接相互作用的增加。我们假设非连接性Cx43/微管复合对于GSC的维持和存活至关重要，并试图在维持其他Cx43功能（如间隙连接形成）的同时特异性破坏这种相互作用。使用Cx43羧基末端微管蛋白结合结构域的Cx43模拟肽（JM2），我们成功破坏了GSCs中Cx43与微管的相互作用。重要的是，给予JM2显著降低了体外GSC的存活率，并限制了体内GSC来源和GBM患者来源的异种移植肿瘤的生长。总之，这些结果确定JM2是一种在GBM治疗中消融GSCs的新型肽药物。
