Eucalyptal A inhibits glioma by rectifying oncogenic splicing of MYO1B mRNA via suppressing SRSF1 expression
Eucalyptal A inhibits glioma by rectifying oncogenic splicing of MYO1B mRNA via suppressing SRSF1 expression
复制标题
桉树 A 通过抑制 SRSF1 表达来纠正 MYO1B mRNA 的致癌剪接来抑制神经胶质瘤
DOI：
10.1016/j.ejphar.2020.173669
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发表时间：
2021-01-05
影响因子：
5
通讯作者：
Yu, Shizhu
中科院分区：
文献类型：
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作者：
Hua, Dan;Zhao, Qian;Yu, Shizhu
胶质瘤是最常见的原发性颅内肿瘤，其中胶质母细胞瘤（GBM）的恶性程度和致死率最高。然而，目前的化疗药物对于GBM的治疗仍不能令人满意。作为主要从桉树物种中提取的天然产物，间苯三酚-萜烯加合物具有作为抗癌先导化合物的潜力，越来越受到人们的关注。为了发现具有抗GBM能力的新先导化合物，我们从E. globulus的果实中分离出具有间苯三酚-萜烯骨架的Eucalyptal A，并研究了其体外和体内的抗GBM活性。从功能上讲，我们在体外验证了桉叶素 A 可以抑制 GBM 细胞的增殖、生长和侵袭。此外，Eucalyptal A 在荷瘤小鼠体内具有与体外相同的抗 GBM 活性，并通过维持小鼠体重来延长总生存时间。进一步的机制研究表明，Eucalyptal A 下调 SRSF1 表达并纠正 SRSF1 引导的 MYO1B mRNA 异常选择性剪接，从而通过 PDK1/AKT/c-Myc 和 PAK/Cofilin 轴产生抗 GBM 活性。综上所述，我们确定桉树 A 是一种重要的抗 GBM 先导化合物，代表了神经胶质瘤治疗的新方向。
Glioma is the most common primary intracranial tumor, in which glioblastoma (GBM) is the most malignant and lethal. However, the current chemotherapy drugs are still unsatisfactory for GBM therapy. As the natural products mainly extracted from Eucalyptus species, phloroglucinol-terpene adducts have the potential to be anticancer lead compounds that attracted increasing attention. In order to discover the new lead compounds with the anti-GBM ability, we isolated Eucalyptal A with a phloroglucinol-terpene skeleton from the fruit of E. globulus and investigated its anti-GBM activity in vitro and in vivo. Functionally, we verified that Eucalyptal A could inhibit the proliferation, growth and invasiveness of GBM cells in vitro. Moreover, Eucalyptal A had the same anti-GBM activity in tumor-bearing mice as in vitro and prolonged the overall survival time by maintaining mice body weight. Further mechanism research revealed that Eucalyptal A downregulated SRSF1 expression and rectified SRSF1-guided abnormal alternative splicing of MYO1B mRNA, which led to anti-GBM activity through the PDK1/AKT/c-Myc and PAK/Cofilin axes. Taken together, we identified Eucalyptal A as an important antiGBM lead compound, which represents a novel direction for glioma therapy.