Sbiera, Silviu and Leich, Ellen and Liebisch, Gerhard and Sbiera, Iuliu and Schirbel, Andreas and Wiemer, Laura and Matysik, Silke and Eckhardt, Carolin and Gardill, Felix and Gehl, Annemarie and Kendl, Sabine and Weigand, Isabel and Bala, Margarita and Ronchi, Cristina L. and Deutschbein, Timo and Schmitz, Gerd and Rosenwald, Andreas and Allolio, Bruno and Fassnacht, Martin and Kroiss, Matthias (2015) Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells. ENDOCRINOLOGY, 156 (11). pp. 3895-3908. ISSN 0013-7227, 1945-7170
Full text not available from this repository. (Request a copy)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 NCl-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 factor2A(elF2 alpha) phosphorylation were activated by mitotane in NCl-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 NCl-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | UNFOLDED PROTEIN RESPONSE; CHOLESTERYL ESTER; ADJUVANT MITOTANE; CANCER; MITOCHONDRIA; ACAT; ACTIVATION; QUANTIFICATION; METABOLISM; EXPRESSION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 May 2019 08:22 |
| Last Modified: | 06 May 2019 08:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4486 |
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