Inhibition of insulin/IGF-1 receptor signaling enhances bile acid toxicity in primary hepatocytes

• Published in: Biochemical pharmacology 2005-11, Vol.70 (11), p.1685-1696
• Main Authors: Dent, Paul, Han, Song Iy, Mitchell, Clint, Studer, Elaine, Yacoub, Adly, Grandis, Jennifer, Grant, Steven, Krystal, Geoffrey W., Hylemon, Philip B.
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Apoptosis; Apoptosis - drug effects; Bile acid; Bile Acids and Salts - toxicity; Biological and medical sciences; Cells, Cultured; Deoxycholic Acid - toxicity; Dominant negative; Drug toxicity and drugs side effects treatment; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Expression Regulation - drug effects; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Insulin; Insulin - pharmacology; Insulin Antagonists - pharmacology; Intermediary metabolites. Miscellaneous; Kinase; Male; Medical sciences; Mice; Mice, Inbred C57BL; Other biological molecules; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptor; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - metabolism; Signal Transduction - drug effects; Toxicity: digestive system
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2005.08.020

Modulation of ERBB and insulin-like growth factor 1 (IGF-1) receptor function is recognized as a potential mechanism to inhibit tumor growth. We and others have shown that inhibition of ERBB1 can enhance bile acid toxicity. Herein, we extend our analyses to examine the impact of insulin/IGF-1 receptor inhibition on primary hepatocyte survival when exposed to the secondary bile acid deoxycholic acid (DCA) and compare the impact inhibition of this receptor has on bile acid toxicity effects to that of ERBB1/MEK1/2 inhibition. The insulin/IGF-1 receptor inhibitor NVP-ADW742 at concentrations which inhibit both the insulin and IGF-1 receptors had a modest negative impact on hepatocyte viability, and strongly potentiated DCA-induced apoptotic cell death. Identical data were obtained expressing a dominant negative IGF-1 receptor in hepatocytes; a receptor which acts to inhibit both the IGF-1 receptor and the insulin receptor in trans. Inhibition of ERBB1 function using Iressa (gefitinib) or the tyrphostin AG1478 had more modest effects at enhancing DCA lethality than inhibition of the insulin/IGF-1 receptor function. In contrast, over-expression of a dominant negative ERBB1 protein had pleiotropic effects on multiple signaling pathways in an apparently non-specific manner. These findings suggest that novel therapeutic kinase inhibitors, targeted against growth factor receptors, have the potential to promote bile acid toxicity in hepatocyte when bile flow may be impaired.