Inhibition of hypoxia-inducible factor 1α accumulation by glyceryl trinitrate and cyclic guanosine monophosphate
| العنوان: | Inhibition of hypoxia-inducible factor 1α accumulation by glyceryl trinitrate and cyclic guanosine monophosphate |
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| المؤلفون: | Jean-François Paré, Ivraym B. Barsoum, Harrison Loh, Judy Kim, D. Robert Siemens, Charles H. Graham |
| المصدر: | Bioscience Reports |
| بيانات النشر: | Portland Press Ltd., 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Biophysics, Nitric Oxide, Biochemistry, Nitric oxide, Hydroxylation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, DU145, Cell Line, Tumor, Tumor Microenvironment, Humans, Nitric Oxide Donors, Cyclic GMP, Molecular Biology, Cyclic guanosine monophosphate, Transcription factor, Research Articles, Cancer, Calpastatin, hypoxia inducible factors, biology, hypoxia, Calpain, Chemistry, Prostatic Neoplasms, Cell Biology, Hypoxia-Inducible Factor 1, alpha Subunit, Therapeutics & Molecular Medicine, nitroglycerin, 3. Good health, Cell biology, cGMP, 030104 developmental biology, Hypoxia-inducible factors, 030220 oncology & carcinogenesis, biology.protein, Tumor Hypoxia, Signal Transduction |
| الوصف: | A key mechanism mediating cellular adaptive responses to hypoxia involves the activity of hypoxia-inducible factor 1 (HIF-1), a transcription factor composed of HIF-1α, and HIF-1β subunits. The classical mechanism of regulation of HIF-1 activity involves destabilisation of HIF-1α via oxygen-dependent hydroxylation of proline residues and subsequent proteasomal degradation. Studies from our laboratory revealed that nitric oxide (NO)-mediated activation of cyclic guanosine monophosphate (cGMP) signalling inhibits the acquisition of hypoxia-induced malignant phenotypes in tumour cells. The present study aimed to elucidate a mechanism of HIF-1 regulation involving NO/cGMP signalling. Using human DU145 prostate cancer cells, we assessed the effect of the NO mimetic glyceryl trinitrate (GTN) and the cGMP analogue 8-Bromo-cGMP on hypoxic accumulation of HIF-1α. Concentrations of GTN known to primarily activate the NO/cGMP pathway (100 nM–1 µM) inhibited hypoxia-induced HIF-1α protein accumulation in a time-dependent manner. Incubation with 8-Bromo-cGMP (1 nM–10 µM) also attenuated HIF-1α accumulation, while levels of HIF-1α mRNA remained unaltered by exposure to GTN or 8-Bromo-cGMP. Furthermore, treatment of cells with the calpain (Ca2+-activated proteinase) inhibitor calpastatin attenuated the effects of GTN and 8-Bromo-cGMP on HIF-1α accumulation. However, since calpain activity was not affected by incubation of DU145 cells with various concentrations of GTN or 8-Bromo-cGMP (10 nM or 1 µM) under hypoxic or well-oxygenated conditions, it is unlikely that NO/cGMP signalling inhibits HIF-1α accumulation via regulation of calpain activity. These findings provide evidence for a role of NO/cGMP signalling in the regulation of HIF-1α, and hence HIF-1-mediated hypoxic responses, via a mechanism dependent on calpain. |
| تدمد: | 1573-4935 0144-8463 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c2d8ba1919692c8f16fd6e71538823e3 https://doi.org/10.1042/bsr20192345 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c2d8ba1919692c8f16fd6e71538823e3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15734935 01448463 |
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