Despite aggressive treatment, the recurrence of glioma is an inevitable occurrence, leading to unsatisfactory clinical outcomes. A plausible explanation for this phenomenon is the phenotypic alterations that glioma cells undergo aggressive therapies, such as TMZ-therapy. However, the underlying mechanisms behind these changes are not well understood. The TMZ chemotherapy resistance model was employed to assess the expression of intercellular adhesion molecule-1 (ICAM1) in both in vitro and in vivo settings. The potential role of ICAM1 in regulating TMZ chemotherapy resistance was investigated through knockout and overexpression techniques. Furthermore, the mechanism underlying ICAM1-mediated TMZ chemotherapy resistance was examined using diverse molecular biological methods, and the lipid raft protein was subsequently isolated to investigate the cellular subcomponents where ICAM1 operates. Acquired TMZ resistant (TMZ-R) glioma models heightened production of intercellular adhesion molecule-1 (ICAM1) in TMZ-R glioma cells. Additionally, we observed a significant suppression of TMZ-R glioma proliferation upon inhibition of ICAM1, which was attributed to the enhanced intracellular accumulation of TMZ. Our findings provide evidence supporting the role of ICAM1, a proinflammatory marker, in promoting the expression of ABCB1 on the cell membrane of TMZ-resistant cells. We have elucidated the mechanistic pathway by which ICAM1 modulates phosphorylated moesin, leading to an increase in ABCB1 expression on the membrane. Furthermore, our research has revealed that the regulation of moesin by ICAM1 was instrumental in facilitating the assembly of ABCB1 exclusively on the lipid raft of the membrane. Our findings suggest that ICAM1 is an important mediator in TMZ-resistant gliomas and targeting ICAM1 may provide a new strategy for enhancing the efficacy of TMZ therapy against glioma.

中文翻译：

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细胞间粘附分子-1通过增加膜上ABCB1的组装来抑制获得性TMZ耐药神经胶质瘤的TMZ化学敏感性


尽管积极治疗，神经胶质瘤的复发是不可避免的，导致临床结果不令人满意。这种现象的一个合理解释是神经胶质瘤细胞接受积极治疗（例如 TMZ 治疗）后发生的表型改变。然而，这些变化背后的潜在机制尚不清楚。采用 TMZ 化疗耐药模型来评估体外和体内细胞间粘附分子 1 (ICAM1) 的表达。通过敲除和过表达技术研究了 ICAM1 在调节 TMZ 化疗耐药中的潜在作用。此外，使用多种分子生物学方法检查了 ICAM1 介导的 TMZ 化疗耐药机制，随后分离出脂筏蛋白以研究 ICAM1 发挥作用的细胞亚成分。获得性 TMZ 耐药 (TMZ-R) 神经胶质瘤模型提高了 TMZ-R 神经胶质瘤细胞中细胞间粘附分子 1 (ICAM1) 的产生。此外，我们观察到抑制 ICAM1 后 TMZ-R 神经胶质瘤增殖显着受到抑制，这归因于 TMZ 细胞内积累的增强。我们的研究结果提供了支持 ICAM1（一种促炎标记物）在促进 TMZ 耐药细胞细胞膜上 ABCB1 表达中作用的证据。我们已经阐明了 ICAM1 调节磷酸化 moesin 从而导致膜上 ABCB1 表达增加的机制途径。此外，我们的研究表明，ICAM1 对 moesin 的调节有助于促进 ABCB1 仅在膜的脂筏上组装。 我们的研究结果表明，ICAM1 是 TMZ 耐药性胶质瘤的重要介质，靶向 ICAM1 可能为增强 TMZ 治疗胶质瘤的疗效提供新策略。