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Cited by 215Natural Compounds in Disease TreatmentInflammasome and immune disordersCell death mechanisms and regulation

Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ

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Cai, Jing, Yi, Mei, Tan, Yixin, Li, Xiaoling, Li, Guiyuan, Zeng, Zhaoyang, Xiong, Wei, Xiang, Bo·2021·Journal of Experimental & Clinical Cancer Research
DOI 10.1186/s13046-021-01995-7PMC PMC8188724
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Abstract

Background: Pyroptosis is a lytic cell death form executed by gasdermins family proteins. Induction of tumor pyroptosis promotes anti-tumor immunity and is a potential cancer treatment strategy. Triptolide (TPL) is a natural product isolated from the traditional Chinese herb which possesses potent anti-tumor activity in human cancers. However, its role in pyroptosis remains to be elucidated. Methods: Cell survival was measured by colony formation assay. Cell apoptosis was determined by Annexin V assay. Pyroptosis was evaluated by morphological features and release of interleukin 1β and lactate dehydrogenase A (LDHA). Immunofluorescence staining was employed to measure subcellular localization of proteins. Tumorigenicity was assessed by a xenograft tumor model. Expression levels of mRNAs or proteins were determined by qPCR or western blot assay, respectively. Results: Triptolide eliminates head and neck cancer cells through inducing gasdermin E (GSDME) mediated pyroptosis. Silencing GSDME attenuates the cytotoxicity of TPL against cancer cells. TPL treatment suppresses expression of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells, leading to activation of the BAD/BAX-caspase 3 cascade and cleavage of GSDME by active caspase 3. Silencing HK-II sensitizes cancer cells to TPL induced pyroptosis, whereas enforced expression of HK-II prevents TPL induced pyroptosis. Mechanistically, HK-II prevents mitochondrial translocation of BAD, BAX proteins and activation of caspase 3, thus attenuating cleavage of GSDME and pyroptosis upon TPL treatment. Furthermore, TPL treatment suppresses NRF2/SLC7A11 (also known as xCT) axis and induces reactive oxygen species (ROS) accumulation, regardless of the status of GSDME. Combination of TPL with erastin, an inhibitor of SLC7A11, exerts robust synergistic effect in suppression of tumor survival in vitro and in a nude mice model. Conclusions: This study not only provides a new paradigm of TPL in cancer therapy, but also highlights a crucial role of mitochondrial HK-II in linking glucose metabolism with pyroptosis.

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  • Treatment with triptolide results in morphological alterations characterized by cytoplasmic swelling and membrane disruption, as well as marked elevation in mRNA and protein expression of GSDME and GSDMB.

    “Treatment with TPL resulted in morphological alterations characterized by cytoplasmic swelling and membrane disruption, as well as a marked elevation in the mRNA and protein expression of gasdermin E (GSDME) and GSDMB.”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [89]

    The Results section ('TPL induced cancer cells pyroptosis is mediated by GSDME'; page unavailable) supports TPL-induced cytoplasmic swelling and membrane rupture in the head and neck cancer cells studied. It reports GSDME cleavage after treatment, but describes GSDME and GSDMB expression as baseline measurements, not marked increases in their mRNA and protein expression caused by TPL. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Cells exposed to triptolide undergo non-apoptotic cell death.

    “Specifically, cells exposed to TPL were found to undergo non-apoptotic cell death.”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [89]

    The Results section ('TPL induced pyroptotic cell death in head and neck cancer cells') reports non-apoptotic cell death after triptolide treatment in HK1 and FaDu cells. The claim is broader than those findings: the same passage says C666–1 cells did not show robust cell death after treatment. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Selective inhibition of GSDME counteracts triptolide-induced cell death and mitigates cytoplasmic swelling and membrane disruption.

    “Selective inhibition of GSDME was found to counteract TPL-induced cell death and mitigated cytoplasmic swelling and membrane disruption.89”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [89]

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  • Drug repurposing for cancer therapy

    Xia, Y., Sun, M., Huang, H., & Jin, W.-L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01808-1 · Cited by 443 · see citing works

    “89 In addition to pyroptosis, Wang and colleagues also found that the use of TPL-loaded polyethylene glycol (PEG) nanocarriers induced necrosis and enhanced the sensitivity of MIA PaCa-2 (pancreatic ductal adenocarcinoma) tumors to gemcitabine.”
    Background

Authors
Cai, J., Yi, M., Tan, Y., Li, X., Li, G., Zeng, Z., Xiong, W., & Xiang, B.
Affiliations
Central South University (CN)
Corresponding author
Xiang, Bo
ORCID
Venue
Journal of Experimental & Clinical Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2021-06-09
Volume
40
Issue
1
Pages
190-190
ISSN
  • 0392-9078 (ISSN-L)
  • 1756-9966
DOI
10.1186/s13046-021-01995-7
PMC
PMC8188724
OpenAlex
W4200428404
Cited by
215
References
2
Citations by year
2026: 36 · 2025: 42 · 2024: 39 · 2023: 58 · 2022: 34 · 2021: 6
FWCI
39.91
Type
journal article
Language
en
Update notices
correction (2021-09-22)
Open access
Licence
Locations
  • Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81772902, 81872278, 81703131, 82072596)
  • Natural Science Foundation of Hunan Province (2018JJ1040, 2020JJ4920, 2020JJ4838, 2020JJ4766, 2020JJ3055)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
triptolide, pyroptosis, gasdermin E, head and neck cancer, c-Myc, caspase-3, SLC7A11, reactive oxygen species, glucose metabolism, erastin, combination therapy, xenograft tumor model
MeSH terms
Pyroptosis, Animals, Biological Products, Diterpenes, Epoxy Compounds, Head and Neck Neoplasms, Hexokinase, Humans, Immunosuppressive Agents, Male, Mice, Nude, Mitochondria, Phenanthrenes, Transfection, Cell Line, Tumor, Mice

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