Activation of prolyl hydroxylase-2 for stabilization of mitochondrial stress along with simultaneous downregulation of HIF-1α/FASN in ER + breast cancer subtype.

Abstract

The present study was undertaken to inquest the chemical activation of prolyl hydroxylase-2 for the curtailment of hypoxia-inducible factor-1α and fatty acid synthase. It was well documented that hypoxia-inducible factor-1α and fatty acid synthase were overexpressed in mammary gland carcinomas. After screening a battery of compounds, BBAP-2 was retrieved as a potential prolyl hydroxylase-2 activator and validates its activity using ER + MCF-7 cell line and n-methyl-n-nitrosourea-induced rat in vivo model, respectively. BBAP-2 was palpable for the morphological characteristics of apoptosis along with changes in the mitochondrial intergrity as visualized by acridine orange/ethidium bromide and JC-1 staining against ER + MCF-7 cells. BBAP-2 also arrest the cell cycle of ER + MCF-7 cells at G2/M phase. Afterward, BBAP-2 has scrutinized against n-methyl-n-nitrosourea-induced mammary gland carcinoma in albino Wistar rats. BBAP-2 restored the morphological architecture when screened through carmine staining, haematoxylin and eosin staining, and scanning electron microscopy. BBAP-2 also delineated the markers of oxidative stress favourably. The immunoblotting and mRNA expression analysis validated that BBAP-2 has a potentialty activate the prolyl hydroxylase-2 with sequential downregulating effect on hypoxia-inducible factor-1α and its downstream checkpoint. BBAP-2 also fostered apoptosis through mitochondrial-mediated death pathway. The present study elaborates the chemical activation of prolyl hydroxylase-2 by which the increased expression of HIF-1α and FASN can be reduced in mammary gland carcinoma.

• Authors: Uma Devi, Manjari Singh, Subhadeep Roy, Pushpraj S Gupta, Mohd Nazam Ansari, Abdulaziz S Saeedan, Gaurav Kaithwas
• Journal: Cell biochemistry and function (Cell Biochem Funct) Vol. 37 Issue 4 Pg. 216-227 (Jun 2019) ISSN: 1099-0844 [Electronic] England
• PMID: 30950543 (Publication Type: Journal Article)
• Copyright: © 2019 John Wiley & Sons, Ltd.

Chemical References

• Antineoplastic Agents
• Benzopyrans
• 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 (chemistry, pharmacology)
• Apoptosis (drug effects)
• Benzopyrans (chemistry, pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Drug Screening Assays, Antitumor
• Enzyme Activation (drug effects)
• 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, metabolism, pathology)
• Mitochondria (drug effects, metabolism, pathology)
• Rats
• Rats, Wistar
• Receptors, Estrogen (metabolism)