| Title: |
Sanguinarine Induces Necroptosis of HCC by Targeting PKM2 Mediated Energy Metabolism. |
| Authors: |
Kong, Rui1 (AUTHOR), Wang, Nan2,3 (AUTHOR) wanrong1970@163.com, Zhou, Chunli1 (AUTHOR), Zhou, Yuqing1 (AUTHOR), Guo, Xiaoyan4 (AUTHOR), Wang, Dongyan4 (AUTHOR), Shi, Yihai4 (AUTHOR), Wan, Rong3 (AUTHOR), Zheng, Yuejuan5 (AUTHOR) zhengyj@shutcm.edu.cn, Lu, Jie3,4 (AUTHOR) zhengyj@shutcm.edu.cn |
| Source: |
Cancers. Jul2024, Vol. 16 Issue 14, p2533. 19p. |
| Subject Terms: |
*COMPUTER-assisted molecular modeling, *BIOLOGICAL models, *FLOW cytometry, *IN vitro studies, *TISSUE arrays, *RESEARCH funding, *COLONY-forming units assay, *GLYCOLYSIS, *PHOSPHORYLATION, *MITOCHONDRIA, *T-test (Statistics), *DATA analysis, *HOMEOSTASIS, *ANTINEOPLASTIC agents, *ELECTRON microscopy, *APOPTOSIS, *CELL proliferation, *PHYTOCHEMICALS, *TUMOR markers, *CYTOSKELETAL proteins, *CELLULAR signal transduction, *REVERSE transcriptase polymerase chain reaction, *DESCRIPTIVE statistics, *IN vivo studies, *FLUORESCENT antibody technique, *ENERGY metabolism, *CELL lines, *MICE, *METASTASIS, *REACTIVE oxygen species, *IMMUNOHISTOCHEMISTRY, *CELL death, *ANIMAL experimentation, *WESTERN immunoblotting, *GENE expression profiling, *ONE-way analysis of variance, *STATISTICS, *MOLECULAR structure, *STAINS & staining (Microscopy), *DATA analysis software, *HEPATOCELLULAR carcinoma, *SEQUENCE analysis, *PRECIPITIN tests, *PHARMACODYNAMICS |
| Abstract: |
Simple Summary: Here, we show that the plant-derived product, sanguinarine, inhibited aerobic glycolysis and oxidative phosphorylation; which resulted in energy alternations and necroptosis of tumor cells. Moreover, we identify the PKM2/β-catenin axis as the main target in sanguinarine treatment against HCC development. Backgrounds: Abnormal metabolism is the hallmark of hepatocellular carcinoma. Targeting energy metabolism has become the major focus of cancer therapy. The natural product, sanguinarine, displays remarkable anti-tumor properties by disturbing energy homeostasis; however, the underlying mechanism has not yet been elucidated. Methods: The anticancer activity of sanguinarine was determined using CCK-8 and colony formation assay. Morphological changes of induced cell death were observed under electron microscopy. Necroptosis and apoptosis related markers were detected using western blotting. PKM2 was identified as the target by transcriptome sequencing. Molecular docking assay was used to evaluate the binding affinity of sanguinarine to the PKM2 molecule. Furthermore, Alb-CreERT2; PKM2loxp/loxp; Rosa26RFP mice was used to construct the model of HCC—through the intervention of sanguinarine in vitro and in vivo—to accurately explore the regulation effect of sanguinarine on cancer energy metabolism. Results: Sanguinarine inhibited tumor proliferation, metastasis and induced two modes of cell death. Molecular docking of sanguinarine with PKM2 showed appreciable binding affinity. PKM2 kinase activity and aerobic glycolysis rate declined, and mitochondrial oxidative phosphorylation was inhibited by sanguinarine application; these changes result in energy deficits and lead to necroptosis. Additionally, sanguinarine treatment prevents the translocation of PKM2 into the nucleus and suppresses the interaction of PKM2 with β-catenin; the transcriptional activity of PKM2/β-catenin signaling and its downstream genes were decreased. Conclusions: Sanguinarine showed remarkable anti-HCC activity via regulating energy metabolism by PKM2/β-catenin signaling. On the basis of these investigations, we propose that sanguinarine might be considered as a promising compound for discovery of anti-HCC drugs. [ABSTRACT FROM AUTHOR] |
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