7-ketocholesterol and 27-hydroxycholesterol decreased doxorubicin sensitivity in breast cancer cells: estrogenic activity and mTOR pathway

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F75010330%3A_____%2F17%3A00011804" target="_blank" >RIV/75010330:_____/17:00011804 - isvavai.cz</a>

Result on the web

<a href="http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path" target="_blank" >http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.18632/oncotarget.19789" target="_blank" >10.18632/oncotarget.19789</a>

Result language

angličtina

Original language name

7-ketocholesterol and 27-hydroxycholesterol decreased doxorubicin sensitivity in breast cancer cells: estrogenic activity and mTOR pathway

Original language description

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) alpha/ER beta 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 ER alpha(-) 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 ER alpha knockdown. In a yeast reporter assay, the ER alpha 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 ER alpha- and mTOR-dependent pathway. The 7-KC- and 27-HC-elicited estrogenic effects are crucial in the P-glycoprotein induction in breast cancer cells.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30101 - Human genetics

Project

<a href="/en/project/GC13-25222J" target="_blank" >GC13-25222J: Role of oxysterols, antiestrogens and phytoestrogens in drug resistance of cancer cells in patients and experimental models</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Oncotarget

ISSN

1949-2553

e-ISSN

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Volume of the periodical

8

Issue of the periodical within the volume

39

Country of publishing house

US - UNITED STATES

Number of pages

18

Pages from-to

66033-66050

UT code for WoS article

000410291200109

EID of the result in the Scopus database

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