Journal
BRITISH JOURNAL OF CANCER
Volume 127, Issue 2, Pages 364-376Publisher
SPRINGERNATURE
DOI: 10.1038/s41416-022-01800-y
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Funding
- National Natural Science Foundation of China [81774191, 82174265]
- International Collaborative of Ministry of Science and Technology [2017YEE0915000]
- National Science Foundation of Shandong Province in China [ZR201911020118, ZR201911110299]
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This study found that plumbagin inhibits glioma growth through targeting NQO1/GPX4-mediated ferroptosis, suggesting its potential as a novel inducer or candidate for anti-glioma therapy.
Background Ferroptosis has attracted increasing interest in cancer therapy. Emerging evidences suggest that naturally occurring naphthoquinones exhibit potent anti-glioma effects via various mechanisms. Methods The anti-glioma effects of plumbagin were evaluated by in vitro and in vivo experiments. Anti-glioma mechanism of plumbagin was studied by proteomics, flow cytometry, MDA assay, western blot, and RT-PCR. Gene knockdown/overexpression, molecular docking, PharmMappper database, and coimmunoprecipitation were used to study the targets of plumbagin. Results Plumbagin showed higher blood-brain barrier penetration ability than that of lapachol and shikonin and elicited significant growth inhibitory effects in vitro and in vivo. Ferroptosis was the main mechanism of plumbagin-induced cell death. Mechanistically, plumbagin significantly downregulated the protein and mRNA levels of xCT and decreased GPX4 protein levels. NAD(P)H quinone dehydrogenase 1 (NQO1) was revealed as a plumbagin predictive target using PharmMappper database and molecular docking. Plumbagin enhanced NQO1 activity and decreased xCT expression, resulting in NQO1-dependent cell death. It also induced GPX4 degradation via the lysosome pathway and caused GPX4-dependent cell death. Conclusions Plumbagin inhibited in vitro and in vivo glioma growth via targeting NQO1/GPX4-mediated ferroptosis, which might be developed as a novel ferroptosis inducer or anti-glioma candidate.
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