Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
Int J Mol Sci. 2023 Jan 5;24(2):1015. doi: 10.3390/ijms24021015.
The mulberry tree () has been cultivated in China for thousands of years. Mulberry Diels-Alder-type adducts (MDAAs) are characteristic constituents of the genus Morus. The unique structure and diverse bioactivities of MDAAs have attracted the attention of researchers. Kuwanon M (KWM) is an MDAA isolated from the root bark of . This research reports the growth inhibitory effects of KWM on human lung cancer cells and its possible mechanism. In A549 and NCI-H292 cells, KWM treatment induced suppression of cell proliferation and migration. The appearance of chromatin condensation, phosphatidyl serine exposure and caspase cleavage indicated the arising of apoptosis. The loss of mitochondrial membrane potential (MMP), release of cytochrome and dysregulation of Bax/Bcl-2 demonstrated that the KWM-induced apoptosis was through the mitochondrial pathway. Paraptosis was simultaneously detected under KWM treatment, as evidenced by the exhibition of cytoplasmic vacuolation, down-regulation of Alix and up-regulation of endoplasmic reticulum (ER) stress-related proteins. Mechanistically, ER stress induced activation of unfolded protein response (UPR) pathways and activation of the MAPK (JNK and ERK) pathway, all of which were critical for KWM-induced apoptosis and paraptosis. These findings suggested the possibility that KWM might be considered as a potential lung cancer therapeutic agent.
桑树在中国已经被种植了数千年。桑德氏二萜类加合物（MDAAs）是桑属植物的特征成分。MDAAs 的独特结构和多样的生物活性引起了研究人员的关注。昆诺酮 M（KWM）是从桑树根皮中分离得到的一种 MDAAs。本研究报告了 KWM 对人肺癌细胞的生长抑制作用及其可能的机制。在 A549 和 NCI-H292 细胞中，KWM 处理诱导细胞增殖和迁移抑制。染色质浓缩、磷脂酰丝氨酸暴露和半胱天冬酶切割的出现表明细胞凋亡的发生。线粒体膜电位（MMP）的丧失、细胞色素的释放以及 Bax/Bcl-2 的失调表明 KWM 诱导的细胞凋亡是通过线粒体途径发生的。在 KWM 处理下同时检测到 Paraptosis，其特征是细胞质空泡化、Alix 下调和内质网（ER）应激相关蛋白上调。在机制上，ER 应激诱导未折叠蛋白反应（UPR）途径的激活和 MAPK（JNK 和 ERK）途径的激活，这些都对 KWM 诱导的细胞凋亡和 Paraptosis至关重要。这些发现表明，KWM 可能被认为是一种有潜力的肺癌治疗药物。
