Cholesterol transport system: An integrated cholesterol transport model involved in atherosclerosis

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.

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

Ecto-F1-ATPase/P2Y pathways in metabolic and vascular functions of high density lipoproteins.

https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=4807&context=open_access_pubs

Mouse Low-Grade Gliomas Contain Cancer Stem Cells with Unique Molecular and Functional Properties

https://www.zora.uzh.ch/id/eprint/190125/1/J._Lipid_Res.-2020-Yalcinkaya-492-504.pdf

HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic β-cells in vitro by activation of Smoothened.

The present study was focused on whether ABCG1 deficiency was involved in endothelial apoptosis and its possible mechanism. Human umbilical artery endothelial cells were transfected with ABCG1 siRNA and/or ABCG1 expression plasmid. We observed that silencing of endothelial ABCG1 reduced cholesterol efflux to HDL and increased intracellular lipid content. Moreover, reduction of ABCG1 promoted endothelial apoptosis and expression of endoplasmic reticulum (ER) stress-related molecules GRP78 and CHOP. In contrast, transfection of ABCG1 overexpression plasmid reversed endothelial apoptosis and intracellular lipid accumulation as well as decreased expression of GRP78 and CHOP in ABCG1-deficient endothelial cells. Furthermore, endothelial apoptosis and ER stress-related molecules were induced by repletion of endothelial cells with cholesterol-loaded cyclodextrin, otherwise endothelial apoptotic response and expression of GRP78 and CHOP were suppressed by depletion of cellular cholesterol in ABCG1-deficient endothelial cells. The present results suggest that reduction of ABCG1 induces endothelial apoptosis, which seems associated with intracellular free cholesterol accumulation and subsequent ER stress.

https://link.springer.com/content/pdf/10.1007%2Fs12576-013-0281-8.pdf

ABCG1 deficiency promotes endothelial apoptosis by endoplasmic reticulum stress-dependent pathway

https://heart.bmj.com/content/heartjnl/97/Suppl_3/A50.2.full.pdf

Yongqin Li

Papers

ABCG1 deficiency promotes endothelial apoptosis by endoplasmic reticulum stress-dependent pathway

ATP-binding cassette transporter G1 protects against endothelial dysfunction induced by high glucose