Instituto Estadual Do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro, RJ, 20231-092, Brazil.
Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil.
Cell Mol Neurobiol. 2021 Aug;41(6):1227-1244. doi: 10.1007/s10571-020-00891-6. Epub 2020 Jun 5.
Glioblastoma (GBM) is the most common adult primary tumor of the CNS characterized by rapid growth and diffuse invasiveness into the brain parenchyma. The GBM resistance to chemotherapeutic drugs may be due to the presence of cancer stem cells (CSCs). The CSCs activate the same molecular pathways as healthy stem cells such as WNT, Sonic hedgehog (SHH), and Notch. Mutations or deregulations of those pathways play a key role in the proliferation and differentiation of their surrounding environment, leading to tumorigenesis. Here we investigated the effect of SHH signaling pathway inhibition in human GBM cells by using GANT-61, considering stem cell phenotype, cell proliferation, and cell death. Our results demonstrated that GANT-61 induces apoptosis and autophagy in GBM cells, by increasing the expression of LC3 II and cleaved caspase 3 and 9. Moreover, we observed that SHH signaling plays a crucial role in CSC phenotype maintenance, being also involved in the epithelial-mesenchymal transition (EMT) phenotype. We also noted that SHH pathway modulation can regulate cell proliferation as revealed through the analysis of Ki-67 and c-MYC expressions. We concluded that SHH signaling pathway inhibition may be a promising therapeutic approach to treat patients suffering from GBM refractory to traditional treatments.
胶质母细胞瘤（GBM）是中枢神经系统最常见的成人原发性肿瘤，其特征为快速生长和弥漫性浸润脑实质。GBM 对化疗药物的耐药性可能是由于存在癌症干细胞（CSCs）。CSCs 激活与健康干细胞相同的分子途径，如 WNT、Sonic hedgehog（SHH）和 Notch。这些途径的突变或失调在其周围环境的增殖和分化中起着关键作用，导致肿瘤发生。在这里，我们通过使用 GANT-61 研究了 SHH 信号通路抑制对人 GBM 细胞的影响，考虑到干细胞表型、细胞增殖和细胞死亡。我们的结果表明，GANT-61 通过增加 LC3 II 和裂解的 caspase 3 和 9 的表达，诱导 GBM 细胞凋亡和自噬。此外，我们观察到 SHH 信号在 CSC 表型维持中起着至关重要的作用，也参与上皮-间充质转化（EMT）表型。我们还注意到，SHH 通路的调节可以通过分析 Ki-67 和 c-MYC 的表达来调节细胞增殖。我们得出结论，抑制 SHH 信号通路可能是治疗对传统治疗方法耐药的 GBM 患者的一种有前途的治疗方法。
