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Sanguinarine Induces Necroptosis of HCC by Targeting PKM2 Mediated Energy Metabolism.

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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]
Copyright of Cancers is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Sanguinarine Induces Necroptosis of HCC by Targeting PKM2 Mediated Energy Metabolism.
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– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Cancers is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.3390/cancers16142533
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      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 19
        StartPage: 2533
    Subjects:
      – SubjectFull: COMPUTER-assisted molecular modeling
        Type: general
      – SubjectFull: BIOLOGICAL models
        Type: general
      – SubjectFull: FLOW cytometry
        Type: general
      – SubjectFull: IN vitro studies
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      – SubjectFull: TISSUE arrays
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      – SubjectFull: RESEARCH funding
        Type: general
      – SubjectFull: COLONY-forming units assay
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      – SubjectFull: GLYCOLYSIS
        Type: general
      – SubjectFull: PHOSPHORYLATION
        Type: general
      – SubjectFull: MITOCHONDRIA
        Type: general
      – SubjectFull: T-test (Statistics)
        Type: general
      – SubjectFull: DATA analysis
        Type: general
      – SubjectFull: HOMEOSTASIS
        Type: general
      – SubjectFull: ANTINEOPLASTIC agents
        Type: general
      – SubjectFull: ELECTRON microscopy
        Type: general
      – SubjectFull: APOPTOSIS
        Type: general
      – SubjectFull: CELL proliferation
        Type: general
      – SubjectFull: PHYTOCHEMICALS
        Type: general
      – SubjectFull: TUMOR markers
        Type: general
      – SubjectFull: CYTOSKELETAL proteins
        Type: general
      – SubjectFull: CELLULAR signal transduction
        Type: general
      – SubjectFull: REVERSE transcriptase polymerase chain reaction
        Type: general
      – SubjectFull: DESCRIPTIVE statistics
        Type: general
      – SubjectFull: IN vivo studies
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      – SubjectFull: FLUORESCENT antibody technique
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      – SubjectFull: ENERGY metabolism
        Type: general
      – SubjectFull: CELL lines
        Type: general
      – SubjectFull: MICE
        Type: general
      – SubjectFull: METASTASIS
        Type: general
      – SubjectFull: REACTIVE oxygen species
        Type: general
      – SubjectFull: IMMUNOHISTOCHEMISTRY
        Type: general
      – SubjectFull: CELL death
        Type: general
      – SubjectFull: ANIMAL experimentation
        Type: general
      – SubjectFull: WESTERN immunoblotting
        Type: general
      – SubjectFull: GENE expression profiling
        Type: general
      – SubjectFull: ONE-way analysis of variance
        Type: general
      – SubjectFull: STATISTICS
        Type: general
      – SubjectFull: MOLECULAR structure
        Type: general
      – SubjectFull: STAINS & staining (Microscopy)
        Type: general
      – SubjectFull: DATA analysis software
        Type: general
      – SubjectFull: HEPATOCELLULAR carcinoma
        Type: general
      – SubjectFull: SEQUENCE analysis
        Type: general
      – SubjectFull: PRECIPITIN tests
        Type: general
      – SubjectFull: PHARMACODYNAMICS
        Type: general
    Titles:
      – TitleFull: Sanguinarine Induces Necroptosis of HCC by Targeting PKM2 Mediated Energy Metabolism.
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            – D: 15
              M: 07
              Text: Jul2024
              Type: published
              Y: 2024
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