7-ketocholesterol and 27-hydroxycholesterol decreased doxorubicin sensitivity in breast cancer cells: estrogenic activity and mTOR pathway
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Chun-Wei Wang1,2, Chiung-Chiao Huang1, Pei-Hsin Chou4, Yu-Ping Chang1, Shouzuo Wei5, Frederick Peter Guengerich6, Yueh-Ching Chou3,7,9, Sheng-Fan Wang1,7, Ping-Shan Lai8, Pavel Souček11 and Yune-Fang Ueng1,2,3,10
1National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, R.O.C
2Institute of Biopharmaceutical Sciences, School of Pharmacy, National Yang-Ming University, Taipei, Taiwan, R.O.C
3Department of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C
4Department of Environmental Engineering, National Chung-Kung University, Tainan, Taiwan, R.O.C
5Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
6Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
7Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C
8Department of Chemistry, College of Science, National Chung-Hsin University, Taichung, Taiwan, R.O.C
9Department of Pharmacy, Taipei Medical University, Taipei, Taiwan, R.O.C
10Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan, R.O.C
11Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic
Yune-Fang Ueng, email: [email protected]
Keywords: 7-ketocholesterol, 27-hydroxycholesterol, doxorubicin, P-glycoprotein, estrogen receptor
Received: March 13, 2017 Accepted: June 27, 2017 Published: August 02, 2017
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.
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