Abstract
Oxysterols are 27-carbon oxidation products of cholesterol metabolism. Oxysterols possess several biological actions, including the promotion of cell death. Here, we examined the ability of 7-ketocholesterol (7-KC), cholestane-3β-5α-6β-triol (triol), and a mixture of 5α-cholestane-3β,6β-diol and 5α-cholestane-3β,6α-diol (diol) to promote cell death in a human breast cancer cell line (MDA-MB-231). We determined cell viability, after 24-h incubation with oxysterols. These oxysterols promoted apoptosis. At least part of the observed effects promoted by 7-KC and triol arose from an increase in the expression of the sonic hedgehog pathway mediator, smoothened. However, this increased expression was apparently independent of sonic hedgehog expression, which did not change. Moreover, these oxysterols led to increased expression of LXRα, which is involved in cellular cholesterol efflux, and the ATP-binding cassette transporters, ABCA1 and ABCG1. Diols did not affect these pathways. These results suggested that the sonic hedgehog and LXRα pathways might be involved in the apoptotic process promoted by 7-KC and triol.
Highlights
Cholesterol is an essential component of cell membrane and a precursor of steroid hormones and bile acids [1]
We explore more deeply the apoptotic effect of these cholesterol oxides further by assessing their ability to affect Smoothened (SMO) and Sonic Hedgehog (SHh) expression as well as the expression of LXRα and ABCA1 and ABCG1 transporters, which could be involved in the apoptotic process
Cells incubated with antibodies against LXRα, ABCA1, and ABCG1 were incubated for 1 h with the anti-mouse secondary antibody, R-phycoerythrin (1:1000 dilution; P852- Molecular Probes)
Summary
Cholesterol is an essential component of cell membrane and a precursor of steroid hormones and bile acids [1]. Oxidation promotes the addition of hydroxyl, keto, hyperoxy, carbonyl, or epoxy groups to the cholesterol backbone, mostly at the C4–7 positions or at the C24, 25, and 27 positions of the lateral chain [6] This process generates a large class of different oxysterols. It has been shown that the cytotoxic effect of oxysterols on cells varies according to both the type of oxysterol and the specific cell line [24] This is not surprising considering the large number of molecules within this family and their complex metabolism. We described the cytotoxic effect of 7-ketocholesterol, cholestane-triol, and cholestane-diol on several cell lines [24] These oxysterols inhibited the S phase and stimulated the G0/G1 or G2/M phases. We explore more deeply the apoptotic effect of these cholesterol oxides further by assessing their ability to affect Smoothened (SMO) and Sonic Hedgehog (SHh) expression as well as the expression of LXRα and ABCA1 and ABCG1 transporters, which could be involved in the apoptotic process
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