Background: The hydroxylated derivatives of cholesterol, such as the oxysterols, play important roles in lipid metabolism. In particular, 25-hydroxycholesterol (25HC) has been implicated in a variety of metabolic events including cholesterol homeostasis and atherosclerosis. 25HC is detectable in human plasma after ingestion of a meal rich in oxysterols and following a dietary cholesterol challenge. In addition, the levels of oxysterols, including 25HC, have been found to be elevated in hypercholesterolemic serum. Methodology/Principal Findings: Here, we demonstrate that the estrogen receptor (ER) α mediates gene expression changes and growth responses induced by 25HC in breast and ovarian cancer cells. Moreover, 25HC exhibits the ERα-dependent ability like 17β-estradiol (E2) to inhibit the up-regulation of HIF-1α and connective tissue growth factor by hypoxic conditions in cardiomyocytes and rat heart preparations and to prevent the hypoxia-induced apoptosis. Conclusions/Significance: The estrogen action exerted by 25HC may be considered as an additional factor involved in the progression of breast and ovarian tumors. Moreover, the estrogen-like activity of 25HC elicited in the cardiovascular system may play a role against hypoxic environments. © 2011 Lappano et al.
The cholesterol metabolite 25-Hydroxycholesterol activates estrogen receptor α-Mediated signaling in cancer cells and in cardiomyocytes
de Francesco E. M.;
2011-01-01
Abstract
Background: The hydroxylated derivatives of cholesterol, such as the oxysterols, play important roles in lipid metabolism. In particular, 25-hydroxycholesterol (25HC) has been implicated in a variety of metabolic events including cholesterol homeostasis and atherosclerosis. 25HC is detectable in human plasma after ingestion of a meal rich in oxysterols and following a dietary cholesterol challenge. In addition, the levels of oxysterols, including 25HC, have been found to be elevated in hypercholesterolemic serum. Methodology/Principal Findings: Here, we demonstrate that the estrogen receptor (ER) α mediates gene expression changes and growth responses induced by 25HC in breast and ovarian cancer cells. Moreover, 25HC exhibits the ERα-dependent ability like 17β-estradiol (E2) to inhibit the up-regulation of HIF-1α and connective tissue growth factor by hypoxic conditions in cardiomyocytes and rat heart preparations and to prevent the hypoxia-induced apoptosis. Conclusions/Significance: The estrogen action exerted by 25HC may be considered as an additional factor involved in the progression of breast and ovarian tumors. Moreover, the estrogen-like activity of 25HC elicited in the cardiovascular system may play a role against hypoxic environments. © 2011 Lappano et al.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
