Abstract
Hypercholesterolemia is one of the risk factors for poor outcome in breast cancer therapy. To elucidate the influence of the main circulating oxysterols, cholesterol oxidation products, on the cell-killing effect of doxorubicin, cells were exposed to oxysterols at a subtoxic concentration. When cells were exposed to oxysterols in fetal bovine serum-supplemented medium, 7-ketocholesterol (7-KC), but not 27-hydroxycholesterol (27-HC), decreased the cytotoxicity of doxorubicin in MCF-7 (high estrogen receptor (ER)α/ERβ ratio) cells and the decreased cytotoxicity was restored by the P-glycoprotein inhibitor verapamil. 7-KC stimulated the efflux function of P-glycoprotein and reduced intracellular doxorubicin accumulation in MCF-7 but not in ERα(-) MDA-MB-231 and the resistant MCF-7/ADR cells. In MCF-7 cells, 7-KC increased the mRNA and protein levels of P-glycoprotein. The 7-KC-suppressed doxorubicin accumulation was restored by the fluvestrant and ERα knockdown. In a yeast reporter assay, the ERα activation by 7-KC was more potent than 27-HC. 7-KC, but not 27-HC, stimulated the expression of an ER target, Trefoil factor 1 in MCF-7 cells. When charcoal-stripped fetal bovine serum was used, both 7-KC and 27-HC induced Trefoil factor 1 expression and reduced doxorubicin accumulation in MCF-7 cells. 7-KC-reduced doxorubicin accumulation could be reversed by inhibitors of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin (mTOR). These findings demonstrate that 7-KC decreases the cytotoxicity of doxorubicin through the up-regulation of P-glycoprotein in an ERα- and mTOR-dependent pathway. The 7-KC- and 27-HC-elicited estrogenic effects are crucial in the P-glycoprotein induction in breast cancer cells.
Highlights
Breast cancer is the most common cancer in women worldwide and the 4th most common cancer-related death in Taiwan (“Cancer registry annual report, 2012” reported by Health Promotion Administration, Ministry of Health and Welfare (Taiwan) in 2015)
When cells were exposed to oxysterols in fetal bovine serumsupplemented medium, 7-ketocholesterol (7-KC), but not 27-hydroxycholesterol (27HC), decreased the cytotoxicity of doxorubicin in MCF-7 (high estrogen receptor (ER) α/ERβ ratio) cells and the decreased cytotoxicity was restored by the P-glycoprotein inhibitor verapamil. 7-KC stimulated the efflux function of P-glycoprotein and reduced intracellular doxorubicin accumulation in MCF-7 but not in ERα(-) MDA-MB-231 and the resistant MCF-7/ADR cells
When MCF-7 cells were cultured in DCCFBS-supplemented medium, our findings revealed that both 7-KC and 27-HC stimulated the expression of ER-target gene Trefoil factor 1 (TFF1)
Summary
Breast cancer is the most common cancer in women worldwide and the 4th most common cancer-related death in Taiwan (“Cancer registry annual report, 2012” reported by Health Promotion Administration, Ministry of Health and Welfare (Taiwan) in 2015). Breast cancer patients with higher blood cholesterol had poorer therapeutic outcome [4]. 27-HC was the most abundant oxysterol in most human blood samples and promoted tumor development in ovariectomized breast cancer mouse models [7, 11]. There was no significant difference in serum cholesterol and 27-HC levels between the benign control and breast cancer patients, the mean 27-HC level in normal breast tissues in breast cancer patients was 3-fold higher than in the control group [13]. The 27-HC level was 2-fold higher in tumor than in normal breast tissues. The increased tumor levels of oxysterols, such as 7-KC and 27-HC can be risk factors for the poor outcome in cancer therapy
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