IFN-α-2b induces apoptosis by decreasing cellular cholesterol levels in rat preneoplastic hepatocytes. (September 2020)

• Record Type: Journal Article
• Authors: Quiroga, Ariel D.; Vera, Marina C.; Ferretti, Anabela C.; Lucci, Alvaro; Comanzo, Carla G.; Lambertucci, Flavia; Ceballos, María P.; Carrillo, María C.
• Is Part Of: Cytokine. Volume 133(2020)
• Publication Date: 2020-09
• Subjects: Sterol metabolism -- Hepatocarcinogenesis -- Type I interferon -- Cancer -- Cytokines; IFN-α interferon-α -- AHF altered hepatic foci -- ROS reactive oxygen species -- FC free cholesterol -- CE cholesteryl esters -- HFD high fat diet -- HMGCR 3-hydroxy-3-methylglutaryl coenzyme A reductase -- VLDL very low-density lipoprotein -- DEN diethylnitrosamine -- 2-AAF 2-acetylaminofluorene -- mβCD methyl-β-cyclodextrin -- DMEM Dulbecco's modified Eagle's medium -- IP initiation-promotion or initiated-promoted -- PBS phosphate buffered saline -- TG triacylglycerol; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2020.155172
• Languages: English
• ISSNs: 1043-4666

Abstract

Graphical abstract: Highlights: IFN-α-2b decreases lipid levels in hepatocytes from rats with hepatic preneoplasia. IFN-α-2b induces redistribution of cholesterol in the different cellular organelles. IFN-α-2b treatment affects HMGCR gene and protein expressions and activity. IFN-α-2b-induced action on HMGCR impacts on de novo synthesis of cholesterol. Abstract: IFN-α administration to patients has been long discouraged and pushed back by new and apparently better drugs; however the adverse secondary effect, the high costs and the lack of specific action, make these new drugs hard to be used and put IFN-α again in the eye of the researchers. IFN-α-2b was demonstrated to induce apoptosis and modulation of lipid metabolism and the mechanisms are still unknown. Here, we sought to find the link between these features using a model of early stage cancer development. Using in vitro and in vivo approaches, we evaluated apoptosis and lipid metabolism. IFN-α-2b induced changes in hepatic cholesterol mass due to decreased synthesis and increased secretion. Interestingly, the drop in cellular cholesterol levels was necessary for IFN-α-2b to induce apoptosis. Results presented in this paper show the complexity of the action of IFN-α-2b on the early stages of liver cancer development. We show for the first time an interrelationship between cholesterol, apoptosis and IFN-α-2b. This makes clear the need for a reevaluation of IFN-α-2b action in order to develop softer, safer and more bearable derivatives. In this regard, knowing the molecular mechanisms by which IFN-α exerts its cellular actions is of crucial importance, and it is the main condition for therapy success for classical and new malignancies.