Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling.
Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling.
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结缔组织生长因子通过 TGF-β1 依赖性 Smad/ERK 信号激活促进胶质母细胞瘤中替莫唑胺耐药
DOI：
10.1038/cddis.2017.248
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发表时间：
2017-06-15
影响因子：
9
通讯作者：
Guo H
中科院分区：
文献类型：
--
作者：
Zeng H;Yang Z;Xu N;Liu B;Fu Z;Lian C;Guo H
替莫唑胺（TMZ）治疗胶质母细胞瘤（GB）的有限获益和临床效用经常受到获得性耐药性的影响。克服TMZ耐药和揭示潜在的机制是GB化疗过程中面临的挑战。在这项研究中，我们报告了结缔组织生长因子（CTGF）与GB化疗耐药性和显着上调TMZ处理GB细胞。CTGF敲低促进TMZ诱导的细胞凋亡和增强化疗敏感性，而其过表达显着赋予TMZ抵抗在体外和体内。此外，CTGF通过获得茎样特性促进TMZ抗性，并且CD 44干扰逆转CTGF诱导的TMZ抗性。进一步的研究表明TMZ诱导的CTGF上调是组织生长因子（TGF-β）依赖性的，并通过Smad和ERK 1/2信号通路受TGF-β1激活的调节。总之，我们的研究结果表明CTGF介导的TMZ抗性通过TGF-β1依赖性激活Smad/ERK信号通路发挥关键作用。这些数据为我们提供了识别潜在靶点的见解，这些靶点有利于克服GB中的TMZ耐药性。
Limited benefits and clinical utility of temozolomide (TMZ) for glioblastoma (GB) are frequently compromised by the development of acquired drug resistance. Overcoming TMZ resistance and uncovering the underlying mechanisms are challenges faced during GB chemotherapy. In this study, we reported that connective tissue growth factor (CTGF) was associated with GB chemoresistance and significantly upregulated in TMZ-treated GB cells. CTGF knockdown promoted TMZ-induced cell apoptosis and enhanced chemosensitivity, whereas its overexpression markedly conferred TMZ resistance in vitro and in vivo. Moreover, CTGF promoted TMZ resistance through stem-like properties acquisition and CD44 interference reversed the CTGF-induced TMZ resistance. Mechanistically, further investigation revealed that the TMZ-induced CTGF upregulation was tissue growth factor (TGF-β) dependent, and regulated by TGF-β1 activation through Smad and ERK1/2 signaling. Together, our results suggest a pivotal role of CTGF-mediated TMZ resistance through TGF-β1-dependent activation of Smad/ERK signaling pathways. These data provide us insights for identifying potential targets that are beneficial for overcoming TMZ resistance in GB.
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