BACKGROUND Malignant gliomas are the most frequent primary brain tumors and remain among the most incurable cancers. Although the role of the gap junction protein, connexin43 (Cx43), has been deeply investigated in malignant gliomas, no compounds have been reported with the ability to recapitulate the tumor suppressor properties of this protein in in vivo glioma models. METHODS TAT-Cx43266-283 a cell-penetrating peptide which mimics the effect of Cx43 on c-Src inhibition, was studied in orthotopic immunocompetent and immunosuppressed models of glioma. The effects of this peptide in brain cells were also analyzed. RESULTS While glioma stem cell malignant features were strongly affected by TAT-Cx43266-283, these properties were not significantly modified in neurons and astrocytes. Intraperitoneally administered TAT-Cx43266-283 decreased the invasion of intracranial tumors generated by GL261 mouse glioma cells in immunocompetent mice. When human glioma stem cells were intracranially injected with TAT-Cx43266-283 into immunodeficient mice, there was reduced expression of the stemness markers nestin and Sox2 in human glioma cells at 7 days post-implantation. Consistent with the role of Sox2 as a transcription factor required for tumorigenicity, TAT-Cx43266-283 reduced the number and stemness of human glioma cells at 30 days post-implantation. Furthermore, TAT-Cx43266-283 enhanced the survival of immunocompetent mice bearing gliomas derived from murine glioma stem cells. CONCLUSION TAT-Cx43266-283 reduces the growth, invasion, and progression of malignant gliomas and enhances the survival of glioma-bearing mice without exerting toxicity in endogenous brain cells, which suggests that this peptide could be considered as a new clinical therapy for high-grade gliomas.

中文翻译：

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Connexin43 肽，TAT-Cx43266-283，选择性靶向神经胶质瘤细胞，损害恶性生长，并提高体内小鼠模型的存活率。

背景恶性神经胶质瘤是最常见的原发性脑肿瘤，并且仍然是最无法治愈的癌症之一。尽管间隙连接蛋白 connexin43 (Cx43) 在恶性神经胶质瘤中的作用已得到深入研究，但尚未报道能够在体内神经胶质瘤模型中重现该蛋白质的肿瘤抑制特性的化合物。方法 TAT-Cx43266-283 是一种模拟 Cx43 对 c-Src 抑制作用的细胞穿透肽，在神经胶质瘤的原位免疫活性和免疫抑制模型中进行了研究。还分析了这种肽在脑细胞中的作用。结果虽然神经胶质瘤干细胞的恶性特征受到 TAT-Cx43266-283 的强烈影响，但这些特性在神经元和星形胶质细胞中没有显着改变。腹腔注射 TAT-Cx43266-283 可降低免疫活性小鼠中由 GL261 小鼠神经胶质瘤细胞产生的颅内肿瘤的侵袭。当人类神经胶质瘤干细胞与 TAT-Cx43266-283 一起颅内注射到免疫缺陷小鼠中时，在植入后 7 天，人类神经胶质瘤细胞中干性标记物巢蛋白和 Sox2 的表达降低。与 Sox2 作为致瘤性所需的转录因子的作用一致，TAT-Cx43266-283 在植入后 30 天减少了人类神经胶质瘤细胞的数量和干细胞。此外，TAT-Cx43266-283 增强了具有源自鼠神经胶质瘤干细胞的神经胶质瘤的免疫活性小鼠的存活率。结论 TAT-Cx43266-283 减少了生长、侵袭、