ReferenceID 5086
Decursin promotes HIF-1α proteasomal degradation and immune responses in hypoxic tumour microenvironment
Phytomedicine
BACKGROUND: Hypoxia and HIF-1alpha 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 g
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- Reference Id
- 5086
- Evidence Id
- 21676
- Core Evidence Id
- 21676
- Source Reference Id
- 3457
- Herb2 Reference Id
- HBREF004254
- Subject Paper Key
- HBIN022938_32896707
- Pubmed Id
- 32896707
- Doi
- 10.1016/j.phymed.2020.153318
- Paper Title
- Decursin promotes HIF-1α proteasomal degradation and immune responses in hypoxic tumour microenvironment
- Paper Abstract
- BACKGROUND: Hypoxia and HIF-1alpha 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-1alpha 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-1alpha. STUDY DESIGN: We investigated whether decursin regulates HIF-1alpha 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-1alpha. It increased oxygen-dependant hydroxylation and ubiquitination of HIF-1alpha to promote HIF-1alpha degradation. Decursin also decreased mRNA expression of HIF-1alpha 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-1alpha 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-1alpha 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.
- Journal
- Phytomedicine
- Publish Year
- 2020
- Experiment Subject
- mouse; human; hct116 human colon cancer cells
- Experiment Type
- Cell Experiment
- Phenotype Related
- Colon Cancer; Lung Cancer; Cancer; Lewis Lung Carcinoma; Tumour
- Paper Title Cn
- Paper Title En
- Decursin promotes HIF-1α proteasomal degradation and immune responses in hypoxic tumour microenvironment
- Bilingual Status
- semi_complete