Role of ERK1/2 Signaling in Cinnabarinic Acid-Driven Stanniocalcin 2–Mediated Protection against Alcohol-Induced Apoptosis

• Published in: The Journal of pharmacology and experimental therapeutics 2023-10, Vol.387 (1), p.111-120
• Main Authors: Patil, Nikhil Y., Rus, Iulia, Joshi, Aditya D.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - physiology; Cellular and Molecular; Ethanol - toxicity; Hepatocytes - drug effects; Hepatocytes - metabolism; Intercellular Signaling Peptides and Proteins; Liver - drug effects; Liver - physiopathology; Liver Diseases, Alcoholic - drug therapy; Liver Diseases, Alcoholic - genetics; Liver Diseases, Alcoholic - metabolism; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - physiology; Mice; Oxazines - pharmacology; Oxazines - therapeutic use; Receptors, Aryl Hydrocarbon - agonists
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.123.001670

We have previously shown that a bona fide aryl hydrocarbon receptor (AhR) agonist, cinnabarinic acid (CA), protects against alcohol-induced hepatocyte apoptosis via activation of a novel AhR target gene, stanniocalcin 2 (Stc2). Stc2 translates to a secreted disulfide-linked hormone, STC2, known to function in cell development, calcium and phosphate regulation, angiogenesis, and antiapoptosis—albeit the comprehensive mechanism by which the CA-AhR-STC2 axis confers antiapoptosis is yet to be characterized. In this study, using RNA interference library screening, downstream antiapoptotic molecular signaling components involved in CA-induced STC2-mediated protection against ethanol-induced apoptosis were investigated. RNA interference library screening of kinases and phosphatases in Hepa1 cells and subsequent pathway analysis identified mitogen-activated protein kinase (MAPK) signaling as a critical molecular pathway involved in CA-mediated protection. Specifically, phosphorylation of ERK1/2 was induced in response to CA treatment without alterations in p38 and JNK signaling pathways. Silencing Stc2 in Hepa1 cells and in vivo experiments performed in Stc2−/− (Stc2 knockout) mice, which failed to confer CA-mediated protection against ethanol-induced apoptosis, showed abrogation of ERK1/2 activation, underlining the significance of ERK1/2 signaling in CA-STC2–mediated protection. In conclusion, activation of ERK1/2 signaling in CA-driven AhR-dependent Stc2-mediated protection represents a novel mechanism of protection against acute alcohol-induced apoptosis. Previous studies have shown the role of stanniocalcin 2 (Stc2) in cinnabarinic acid (CA)-mediated protection against alcohol-induced apoptosis. Here, using RNA interference library screening and subsequent in vivo studies, the functional significance of ERK1/2 activation in CA-induced Stc2-mediated protection against acute ethanol-induced apoptosis was identified. This study is thus significant as it illustrates a comprehensive downstream mechanism by which CA-induced Stc2 protects against alcoholic liver disease.