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Cited by 49Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerHepatocellular Carcinoma Treatment and Prognosis

Decursin promotes HIF-1α proteasomal degradation and immune responses in hypoxic tumour microenvironment

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Ge, Yun, Yoon, Soo-Hyun, Jang, Hyeonha, Jeong, Ji-Hak, Lee, You-Mie·2020·Phytomedicine
DOI 10.1016/j.phymed.2020.153318
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Abstract

BACKGROUND: Hypoxia and HIF-1α are important regulators of tumour growth and angiogenesis and could be attractive targets for cancer therapeutics. Decursin is an active compound extracted from the roots of Angelica gigas and has been shown to have potent anti-cancer and anti-angiogenic activities. However, whether decursin regulates HIF-1α activity and immune responses under hypoxic conditions is not yet understood. PURPOSE: The aim of this study was to identify whether decursin exhibits anti-cancer activity by targeting HIF-1α. STUDY DESIGN: We investigated whether decursin regulates HIF-1α protein stability and increases its degradation. In addition, we determined if decursin increases immune responses in tumour microenvironment to identify its hypoxia-associated anti-cancer activities. MATERIALS AND METHODS: We performed the hypoxia-responsive element promoter-reporter assay, Western blot analysis, immune-fluorescence assay, semi-quantitative RT-PCR and ELISA for VEGF secretion, CCK-8 assay for cell proliferation, TUNEL assay for apoptosis and invasion assay in A549 human lung cancer or HCT116 human colon cancer cells. In vivo Lewis lung carcinoma (LLC) allograft mouse model was used to check tumour growth and immune responses in tumour microenvironment by immunohistochemistry analysis. RESULTS: We observed that decursin inhibited HIF-1 activation under hypoxia by down-regulating the protein level of its subunit HIF-1α. It increased oxygen-dependant hydroxylation and ubiquitination of HIF-1α to promote HIF-1α degradation. Decursin also decreased mRNA expression of HIF-1α target genes. Decursin suppressed cancer cell proliferation, induced apoptosis and inhibited cancer cell invasion under hypoxia in cancer cells. In the allograft mouse tumour model, decursin reduced the hypoxic area and HIF-1α and PD-L1 expression. Infiltrating T cells (CD3+), helper T cells (CD4+) and cytotoxic (CD8+) T cells were accumulated, but regulatory T cells (Foxp3) and myeloid-derived suppressor cell-mediated immune suppressors (Arg1) were attenuated by decursin. CONCLUSION: Our results suggest that decursin is a novel HIF-1α inhibitor that functions by promoting its proteasomal degradation and that it also helps improve T cell activation in tumour microenvironment; these findings provide new explanations about its anti-cancer and anti-angiogenic activity mechanisms.

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  • Decursin reduces HIF-1α protein levels and HIF-1-dependent transcriptional activity in hypoxia-exposed human cancer cells.

    “Decursin, a natural coumarin derivative, was shown to reduce HIF-1α protein levels and HIF-1–dependent transcriptional activity in hypoxia-exposed human cancer cells.”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [333]

    The Results section, “Decursin inhibits HIF-1 activity and expression under hypoxic conditions,” reports reduced HIF-1α protein in hypoxic A549 and HCT116 human cancer cells. It also reports reduced HIF-1–dependent luciferase activity under hypoxia, but that transcriptional-activity assay was performed in HEK-293 cells, not the cancer cells. The cancer-cell findings therefore do not support that part of the claim as specifically phrased. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Decursin's reduction of HIF-1α is associated with increased ubiquitination and proteasomal degradation of HIF-1α.

    “This outcome was associated with increased ubiquitination and proteasomal degradation of HIF-1α, resulting in attenuated hypoxia-induced transcriptional activity [333].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [333]

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Authors
Ge, Y., Yoon, S.-H., Jang, H., Jeong, J.-H., & Lee, Y.-M.
Affiliations
Kyungpook National University (KR)
Corresponding author
Lee, You-Mie
ORCID
Venue
Phytomedicine
Publisher
Elsevier BV
Published
2020-11
Volume
78
Pages
153318
ISSN
0944-7113 (ISSN-L)
DOI
10.1016/j.phymed.2020.153318
OpenAlex
W3082417913
Cited by
49
References
36
Citations by year
2026: 5 · 2025: 12 · 2024: 9 · 2023: 5 · 2022: 9 · 2021: 9
FWCI
1.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Phytomedicine (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
National Research Foundation of Korea
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
decursin, HIF-1α, proteasomal degradation, tumor hypoxia, tumor microenvironment, immune response, anticancer activity, Angelica gigas, vascular endothelial growth factor, PD-L1, T cell infiltration, regulatory T cells, myeloid-derived suppressor cells, apoptosis, cell invasion, Lewis lung carcinoma, ubiquitination
MeSH terms
Tumor Hypoxia, A549 Cells, Animals, Antineoplastic Agents, Phytogenic, Benzopyrans, Butyrates, Gene Expression Regulation, Humans, Mice, Inbred C57BL, Down-Regulation, Apoptosis, CD8-Positive T-Lymphocytes, Xenograft Model Antitumor Assays, HCT116 Cells, Cell Proliferation, Hypoxia-Inducible Factor 1, alpha Subunit, Ubiquitination, Tumor Microenvironment, B7-H1 Antigen

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