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

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