PHD-2 activation: a novel strategy to control HIF-1α and mitochondrial stress to modulate mammary gland pathophysiology in ER+ subtype
| Autor: | Avinash C. Tripathi, Pushpraj S Gupta, Gaurav Kaithwas, Abdulaziz S. Saeedan, Manjari Singh, Subhadeep Roy, Nazam Ansari, Shailendra K. Saraf, Uma Devi |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mammary gland Antineoplastic Agents Apoptosis Breast Neoplasms Hypoxia-Inducible Factor-Proline Dioxygenases Flow cytometry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Humans Rats Wistar Pharmacology biology medicine.diagnostic_test Chemistry Acridine orange Mammary Neoplasms Experimental General Medicine Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology Fold change Mitochondria Rats Fatty Acid Synthase Type I Blot Fatty acid synthase 030104 developmental biology medicine.anatomical_structure Receptors Estrogen 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells biology.protein Female Ethidium bromide |
| Zdroj: | Naunyn-Schmiedeberg's Archives of Pharmacology. 392:1239-1256 |
| ISSN: | 1432-1912 0028-1298 |
| DOI: | 10.1007/s00210-019-01658-7 |
| Popis: | Estrogen receptor-positive mammary gland carcinoma and its involvement in regulation of overexpressed hypoxia-inducible factor-1α and fatty acid synthase level in hypoxia influenced cancer cells are the present molecular crosstalk of this entire study. To test the hypothesis, we have proceed our study through chemical activation of prolyl hydroxylase 2 which leads to inhibition of hypoxia-inducible factor-1α and fatty acid synthase in ER+MCF-7 cancer cell line and n-methyl-n-nitrosourea induced mammary gland carcinoma rat model. ER+MCF-7 cells were evident with array of nuclear changes when stained through acridine orange/ethidium bromide. Afterward, JC-1 staining of the cells was evident in mitochondrial depolarization. The cells were arrested in G2/M phase when analyzed with flow cytometry. The morphological analysis of rat mammary gland tissue revealed decrease in alveolar buds, restoration of histopathological features along with intra-arterial cushion. The western blotting and fold change expressions of the genes validating the anticancer efficacy of BBAPH-1 is mediated through mitochondria-mediated apoptosis pathway. BBAPH-1 also modulates the expression of prolyl hydroxylase-2 with significant curtailment of hypoxia-inducible factor-1α, fatty acid synthase expression, and their respective downstream markers. These finding suggest that the BBAP-1-mediated activation of prolyl hydroxylase-2 significantly decreased the level of hypoxia-inducible factor-1α and fatty acid synthase. BBAPH-1 also activates the mitochondria-mediated death apoptosis pathway. |
| Databáze: | OpenAIRE |
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