Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep42860
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Funding
- Hong Kong Baptist University [FRG2/15-16/002]
- Health and Medical Research Fund [HMRF/14130522]
- Research Grants Council [HKBU/12301115, HKBU/204612, HKBU/201913, CityU/11228316]
- French National Research Agency/Research Grants Council Joint Research Scheme [A-HKBU201/12 - Oligoswitch]
- National Natural Science Foundation of China [21575121, 21628502]
- Guangdong Province Natural Science Foundation [2015A030313816]
- Hong Kong Baptist University Century Club Sponsorship Scheme
- Interdisciplinary Research Matching Scheme [RC-IRMS/15-16/03]
- Science and Technology Development Fund, Macao SAR [098/2014/A2]
- University of Macau [MYRG2015-00137-ICMS-QRCM, MYRG2016-00151-ICMS-QRCM, MRG044/LCH/2015/ICMS]
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The hypoxia inducible factor (HIF) pathway has been considered to be an attractive anti-cancer target. One strategy to inhibit HIF activity is through the disruption of the HIF-1 alpha-p300 protein-protein interaction. We report herein the identification of an osmium(II) complex as the first metal-based inhibitor of the HIF-1 alpha-p300 interaction. We evaluated the effect of complex 1 on HIF-1 alpha signaling pathway in vitro and in cellulo by using the dual luciferase reporter assay, co-immunoprecipitation assay, and immunoblot assay. Complex 1 exhibited a dose-dependent inhibition of HRE-driven luciferase activity, with an IC50 value of 1.22 mu M. Complex 1 interfered with the HIF-1 alpha-p300 interaction as revealed by a dose-dependent reduction of p300 co-precipitated with HIF-1 alpha as the concentration of complex 1 was increased. Complex 1 repressed the phosphorylation of SRC, AKT and STAT3, and had no discernible effect on the activity of NF-kappa B. We anticipate that complex 1 could be utilized as a promising scaffold for the further development of more potent HIF-1 alpha inhibitors for anti-cancer treatment.
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