多杀菌素对神经胶质瘤细胞程序性细胞死亡通路的影响。
Effect of doramectin on programmed cell death pathway in glioma cells.
机构信息
Department of Biochemistry and Molecular Biology, College of Life Sciences, Northeast Agricultural University, Harbin, 150030, China.
Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
出版信息
Clin Transl Oncol. 2023 Oct;25(10):2871-2883. doi: 10.1007/s12094-023-03147-z. Epub 2023 Apr 21.
PURPOSE
Doramectin (DRM) is a kind of avermectin drugs, and it has been shown that DRM has anti-cancer effects. However, the molecular mechanism of DRM in programmed cell death (PCD) aspects is still unclear. The objective of this study was to confirm whether DRM induced PCD in glioma cells.
METHODS
In this experiment, the MTT assay and Ki-67 assay were used to detect in vitro cell viability and in vivo tumor proliferation. Then, the effect of DRM on PCD was analyzed by transcriptome comparison. Next, Endogenous apoptosis was detected by transmission electron microscopy (TEM), the DNA gel electrophoresis, JC-1 assay, western blotting and qRT-PCR. Meanwhile, necroptosis was detected by TEM, Hoechst 33342, FITC and PI staining assay, western blotting.
RESULTS
We found DRM induced apoptosis through Bcl-2/Bax/Caspase-3 pathway. And, DRM induced ROS overproduction, then ROS caused necroptosis through RIPK1/RIPK3/MLKL pathway, Mitochondria acted as a bridge between the two pathways.
CONCLUSION
Our research provided new insight with the function of anti-cancer of DRM. These results demonstrated DRM may be used as potential therapeutic agents inducing apoptosis and necroptosis for cancer therapy.
目的
多杀菌素（DRM）是一种阿维菌素类药物，已证实 DRM 具有抗癌作用。然而，DRM 在细胞程序性死亡（PCD）方面的分子机制尚不清楚。本研究旨在证实 DRM 是否诱导神经胶质瘤细胞发生 PCD。
方法
本实验采用 MTT 法和 Ki-67 法检测体外细胞活力和体内肿瘤增殖。然后，通过转录组比较分析 DRM 对 PCD 的影响。接下来，通过透射电子显微镜（TEM）、DNA 凝胶电泳、JC-1 检测、Western blot 和 qRT-PCR 检测细胞内源性凋亡。同时，通过 TEM、Hoechst 33342、FITC 和 PI 染色实验、Western blot 检测坏死性凋亡。
结果
我们发现 DRM 通过 Bcl-2/Bax/Caspase-3 途径诱导细胞凋亡。此外，DRM 诱导 ROS 过度产生，ROS 通过 RIPK1/RIPK3/MLKL 途径引起坏死性凋亡，线粒体在这两种途径之间起桥梁作用。
结论
本研究为 DRM 的抗癌功能提供了新的见解。这些结果表明，DRM 可能被用作诱导细胞凋亡和坏死性凋亡的潜在治疗剂，用于癌症治疗。
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