Department of Neurosurgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
Cell Death Dis. 2017 Jun 15;8(6):e2885. doi: 10.1038/cddis.2017.248.
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.
替莫唑胺（TMZ）治疗胶质母细胞瘤（GB）的疗效有限，且其临床应用价值常受到获得性耐药的影响。克服 TMZ 耐药性并揭示潜在机制是 GB 化疗中面临的挑战。在本研究中，我们报道了结缔组织生长因子（CTGF）与 GB 化疗耐药性相关，且在 TMZ 处理的 GB 细胞中显著上调。CTGF 敲低可促进 TMZ 诱导的细胞凋亡并增强化疗敏感性，而过表达 CTGF 则可显著在体外和体内赋予 TMZ 耐药性。此外，CTGF 通过获得干细胞样特性促进 TMZ 耐药性，而 CD44 干扰则逆转 CTGF 诱导的 TMZ 耐药性。机制研究进一步表明，TMZ 诱导的 CTGF 上调依赖于 TGF-β，且通过 TGF-β1 激活 Smad 和 ERK1/2 信号通路进行调控。综上，我们的研究结果表明 CTGF 通过 TGF-β1 依赖性激活 Smad/ERK 信号通路介导 TMZ 耐药性中发挥关键作用。这些数据为我们提供了新的见解，有助于确定潜在的治疗靶点，以克服 GB 中的 TMZ 耐药性。
