PHD-2 activation: a novel strategy to control HIF-1α and mitochondrial stress to modulate mammary gland pathophysiology in ER+ subtype.

Abstract

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.

• Authors: Uma Devi, Manjari Singh, Subhadeep Roy, Avinash C Tripathi, Pushpraj S Gupta, Shailendra K Saraf, Md Nazam Ansari, Abdulaziz S Saeedan, Gaurav Kaithwas
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 392 Issue 10 Pg. 1239-1256 (10 2019) ISSN: 1432-1912 [Electronic] Germany
• PMID: 31154466 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Receptors, Estrogen
• EGLN1 protein, human
• Hypoxia-Inducible Factor-Proline Dioxygenases
• FASN protein, human
• Fatty Acid Synthase, Type I

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Fatty Acid Synthase, Type I (metabolism)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Hypoxia-Inducible Factor-Proline Dioxygenases (metabolism)
• MCF-7 Cells
• Mammary Neoplasms, Experimental (drug therapy, pathology)
• Mitochondria (metabolism)
• Rats
• Rats, Wistar
• Receptors, Estrogen (metabolism)