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Shikonin from Chinese herbal medicine induces GSDME-controlled pyroptosis in tumor cells

Journal of Traditional Chinese Medical Sciences 2022年第4期9卷 432-442页

作者： Dongxiao Cui Sanjiao Wang Jiajian Guo Mingrui Yang Yunqian Li Yue Zhang Wenfu Ma School of Life Sciences Beijing University of Chinese MedicineBeijing102488China

Objective:To investigate the potential anti-tumor mechanisms of naphthoquinone compound shikonin(SKN)extracted from the root of Chinese herbal medicine plant lithospermum(Lithospermum erythrorhizon Sieb.&Zucc.).Methods:We first observed that SKN treatment led to swelling and bubbles in HeLa cells that were similar to the phenotype of cell ***,the HeLa cells experienced a pyroptotic process with SKN,and this was then assessed using lactate dehydrogenase(LDH)release and propidium iodide(PI)/Hoechst double staining *** is defined as gasdermin-mediated programmed *** identify the potential pyroptosis machinery,two strategies were utilized that included a genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)-associated protein 9 screening experiment and a pyroptosis reconstitution assay executed by each of the five known gasdermins(GSDMA-E).Moreover,endogenous cleavage was also detected in a panel of tumor cell ***:Compared with the control,both the LDH release and PI/Hoechst double-staining experiments suggested that SKN induced perforation and enhancement of the permeability of the cell membranes that resulted in pyroptosis in HeLa cells(P=.028 and P=.032,respectively).In addition,the reconstitution assays in human embryonic kidney 293T(HEK-293T)cells and endogenous cleavage assays in HeLa cells indicated that the pyroptosis was controlled by *** addition,we also found SKN could trigger pyroptosis in a panel of tumor cell lines in which the cellular morphologies were proportional to the GSDME expression ***,the cleavage of GSDME was also detected,and this was indicative of a similar GSDME-mediated ***:Our study not only explained the molecular mechanism of cytotoxicity of SKN to various tumor cells,but also provided additional information for the potential clinical application of natural naphthoquinone compounds against cancer.

关键词： Shikonin naphthoquinone compounds Pyroptosis Gasdermin Anti-tumor activity HeLa cells

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