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Berberine inhibits HIF-1alpha expression via enhanced proteolysis
Shankung Lin1, Shiow-Chwen Tsai, Chun-Chung Lee
1Department of Medical Education and Research, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, Shih Lin, Taipei 111, Taiwan, Republic of China.
Molecular Pharmacology
|August 24, 2004
Summary
Berberine inhibits angiogenesis by destabilizing hypoxia-inducible factor-1alpha (HIF-1alpha) protein, offering potential for cancer therapy. This natural compound blocks tumor-induced blood vessel formation by targeting HIF-1alpha degradation.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Angiogenesis, the formation of new blood vessels, is crucial for tumor growth and metastasis.
- Tumor cells, particularly under hypoxic conditions, secrete factors that promote angiogenesis.
- Berberine, a natural alkaloid, has shown potential therapeutic properties, but its antiangiogenic mechanisms require elucidation.
Purpose of the Study:
- To investigate the antiangiogenic properties of berberine.
- To elucidate the molecular mechanisms underlying berberine's antiangiogenic effects, focusing on its impact on tumor-endothelial cell interactions.
- To determine the role of key angiogenic factors, such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1alpha (HIF-1alpha), in berberine's action.
Main Methods:
- In vitro studies using human umbilical vein endothelial cells (HUVECs) to assess tube formation and migration.
- Modified confrontation culture experiments with gastric adenocarcinoma cells (SC-M1) and HUVECs.
- Western blot and Northern blot analyses to evaluate protein and mRNA expression of VEGF and HIF-1alpha.
- Pulse-chase assays, proteasome inhibition, and immunoprecipitation to investigate HIF-1alpha protein stability and post-translational modifications.
Main Results:
- Berberine directly inhibited in vitro HUVEC tube formation and migration.
- Berberine suppressed the ability of hypoxic SC-M1 cells to stimulate HUVEC migration.
- Berberine prevented the expression of VEGF and HIF-1alpha in hypoxic SC-M1 cells, and HIF-1alpha overexpression reversed berberine's inhibitory effect.
- Berberine induced HIF-1alpha protein degradation, not mRNA down-regulation, via a proteasomal pathway involving lysine acetylation.
Conclusions:
- Berberine exhibits significant antiangiogenic properties by inhibiting endothelial cell function and tumor-induced angiogenesis.
- The antiangiogenic effect of berberine is critically dependent on the repression of HIF-1alpha.
- Berberine triggers HIF-1alpha degradation through a proteasomal pathway modulated by protein acetylation, providing molecular evidence for its potential as an anti-cancer therapeutic agent.