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.