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Endocrinology. 2015 Nov;156(11):3895-908. doi: 10.1210/en.2015-1367. Epub 2015 Aug 25.

Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells.

Author information

1
Department of Internal Medicine I, Endocrinology and Diabetes Unit (S.S., I.S., E.C., F.G., A.G., I.W., M.B., C.L.R., T.D., B.A., M.F.), University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Cancer Center Mainfranken (S.S., A.R., M.F., M.K.), 97080 Würzburg, Germany; Institute of Pathology (E.L., A.R.), University of Würzburg, 97080 Würzburg, Germany; Institute of Clinical Chemistry and Laboratory Medicine (S.M., G.L., G.S.), University Hospital Regensburg, 93053 Regensburg, Germany; Department of Nuclear Medicine (A.S.), University Hospital Würzburg, 97080 Würzburg, Germany; and Clinical Chemistry and Laboratory Medicine (S.K., M.F.), University Hospital Würzburg, 97080 Würzburg, Germany.

Abstract

Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite serious adverse effects, mitotane has been clinically used for decades. Elucidation of its unknown molecular mechanism of action seems essential to develop better ACC therapies. Here, we set out to identify the molecular target of mitotane and altered downstream mechanisms by combining expression genomics and mass spectrometry technology in the NCI-H295 ACC model cell line. Pathway analyses of expression genomics data demonstrated activation of endoplasmic reticulum (ER) stress and profound alteration of lipid-related genes caused by mitotane treatment. ER stress marker CHOP was strongly induced and the two upstream ER stress signalling events XBP1-mRNA splicing and eukaryotic initiation factor 2 A (eIF2α) phosphorylation were activated by mitotane in NCI-H295 cells but to a much lesser extent in four nonsteroidogenic cell lines. Lipid mass spectrometry revealed mitotane-induced increase of free cholesterol, oxysterols, and fatty acids specifically in NCI-H295 cells as cause of ER stress. We demonstrate that mitotane is an inhibitor of sterol-O-acyl-transferase 1 (SOAT1) leading to accumulation of these toxic lipids. In ACC tissue samples we show variable SOAT1 expression correlating with the response to mitotane treatment. In conclusion, mitotane confers adrenal-specific cytotoxicity and down-regulates steroidogenesis by inhibition of SOAT1 leading to lipid-induced ER stress. Targeting of cancer-specific lipid metabolism opens new avenues for treatment of ACC and potentially other types of cancer.

PMID:
26305886
DOI:
10.1210/en.2015-1367
[Indexed for MEDLINE]

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