Regulatory Mechanisms of STAT3 in GBM and its Impact on TMZ Resistance.

Guangyao Lv, Xueying Li, Hongtu Deng, Jianqiao Zhang, Xinfu Gao
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Abstract

STAT3, a key member of the Signal Transducer and Activator of Transcription (STAT) family, plays a vital role in the development and progression of glioblastoma (GBM), as well as in the resistance to the chemotherapy drug temozolomide (TMZ). This review outlines the dysregulation of STAT3 in GBM, focusing on its activation mechanisms and its contribution to TMZ resistance. STAT3 can be activated by cytokines, like IL-6, growth factors, and membrane receptors, like EGFR. In GBM, constitutively active STAT3 enhances tumor growth and therapy resistance. Specifically, resistance to TMZ, a standard chemotherapeutic agent for GBM, is facilitated by STAT3-induced expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase and anti-apoptotic proteins like Bcl-2, as well as through the regulation of microRNAs. To combat TMZ resistance in GBM, strategies that inhibit STAT3 activity have been explored. Recent advancements, such as the use of small molecule inhibitors targeting STAT3 and its upstream or downstream regulators, RNA-based therapies, as well as the development of nanocarriers for targeted delivery of STAT3-targeting small interfering RNA across the blood-brain barrier, have demonstrated significant potential in enhancing the sensitivity of GBM to TMZ. These targeted therapies hold promise for improving the treatment outcomes of patients with GBM.

STAT3在GBM中的调控机制及其对TMZ抗性的影响。
STAT3是信号换能器和转录激活因子(STAT)家族的关键成员,在胶质母细胞瘤(GBM)的发生发展以及对化疗药物替莫唑胺(TMZ)的耐药性中起着至关重要的作用。本文综述了STAT3在GBM中的失调,重点关注其激活机制及其对TMZ耐药的贡献。STAT3可被细胞因子如IL-6、生长因子和膜受体如EGFR激活。在GBM中,组成型活性STAT3促进肿瘤生长和治疗抵抗。具体来说,对GBM标准化疗药物TMZ的耐药是由stat3诱导的DNA修复酶o6 -甲基鸟嘌呤-DNA甲基转移酶和抗凋亡蛋白如Bcl-2的表达以及通过microrna的调控促进的。为了对抗GBM中的TMZ耐药性,研究人员探索了抑制STAT3活性的策略。最近的进展,如使用靶向STAT3及其上游或下游调节因子的小分子抑制剂,基于RNA的治疗,以及开发靶向递送靶向STAT3的小干扰RNA穿过血脑屏障的纳米载体,已经证明了增强GBM对TMZ敏感性的巨大潜力。这些靶向治疗有望改善GBM患者的治疗效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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