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Research ArticleCellular and Molecular

Aryl Hydrocarbon Receptor–Dependent Stanniocalcin 2 Induction by Cinnabarinic Acid Provides Cytoprotection against Endoplasmic Reticulum and Oxidative Stress

Aditya D. Joshi, Dwayne E. Carter, Tod A. Harper Jr. and Cornelis J. Elferink
Journal of Pharmacology and Experimental Therapeutics April 2015, 353 (1) 201-212; DOI: https://doi.org/10.1124/jpet.114.222265
Aditya D. Joshi
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (A.D.J., D.E.C., C.J.E.); and Linus Pauling Institute, Oregon State University, Corvallis, Oregon (T.A.H.)
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Dwayne E. Carter
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (A.D.J., D.E.C., C.J.E.); and Linus Pauling Institute, Oregon State University, Corvallis, Oregon (T.A.H.)
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Tod A. Harper Jr.
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (A.D.J., D.E.C., C.J.E.); and Linus Pauling Institute, Oregon State University, Corvallis, Oregon (T.A.H.)
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Cornelis J. Elferink
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (A.D.J., D.E.C., C.J.E.); and Linus Pauling Institute, Oregon State University, Corvallis, Oregon (T.A.H.)
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Abstract

The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor historically known for its role in xenobiotic metabolism. Although AhR activity has previously been shown to play a cytoprotective role against intrinsic apoptotic stimuli, the underlying mechanism by which AhR confers cytoprotection against apoptosis is largely unknown. Here, we demonstrate that activation of AhR by the tryptophan catabolite cinnabarinic acid (CA) directly upregulates expression of stanniocalcin 2 (Stc2) to elicit cytoprotection against apoptosis induced by endoplasmic reticulum stress and oxidative stress. Chromatin immunoprecipitation studies demonstrated that CA treatment induces direct AhR binding to a region of the Stc2 promoter containing multiple xenobiotic response elements. Using isolated primary hepatocytes from AhR wild-type (AhR floxed) and liver-specific AhR conditional knockout mice, we showed that pretreatment with CA conferred cytoprotection against hydrogen peroxide (H2O2)-, thapsigargin-, and ethanol-induced apoptosis in an AhR-dependent manner. Furthermore, suppressing Stc2 expression using RNA interference confirmed that the cytoprotective properties of CA against H2O2, thapsigargin, and ethanol injury were absolutely dependent on Stc2. Immunochemistry revealed the presence of Stc2 in the endoplasmic reticulum and on the cell surface, consistent with Stc2 secretion and autocrine and/or paracrine signaling. Finally, in vivo data using a mouse model of acute alcohol hepatotoxicity demonstrated that CA provided cytoprotection against ethanol-induced apoptosis, hepatic microvesicular steatosis, and liver injury. Collectively, our data uncovered a novel mechanism for AhR-mediated cytoprotection in the liver that is dependent on CA-induced Stc2 activity.

Footnotes

    • Received December 18, 2014.
    • Accepted February 10, 2015.
  • A.D.J. and D.E.C. contributed equally to this work.

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grants R01-ES007800 and P30-ES006676 (to C.J.E.)].

  • dx.doi.org/10.1124/jpet.114.222265.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 353 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 353, Issue 1
1 Apr 2015
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Research ArticleCellular and Molecular

AhR-Driven Stc2 Expression Confers Cytoprotection

Aditya D. Joshi, Dwayne E. Carter, Tod A. Harper and Cornelis J. Elferink
Journal of Pharmacology and Experimental Therapeutics April 1, 2015, 353 (1) 201-212; DOI: https://doi.org/10.1124/jpet.114.222265

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Research ArticleCellular and Molecular

AhR-Driven Stc2 Expression Confers Cytoprotection

Aditya D. Joshi, Dwayne E. Carter, Tod A. Harper and Cornelis J. Elferink
Journal of Pharmacology and Experimental Therapeutics April 1, 2015, 353 (1) 201-212; DOI: https://doi.org/10.1124/jpet.114.222265
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