Drug-Induced Endoplasmic Reticulum and Oxidative Stress Responses Independently Sensitize Toward TNFα-Mediated Hepatotoxicity
| Autor: | Bram Herpers, Lisa Fredriksson, Mackenzie Hadi, Bob van de Water, Giulia Benedetti, Geny M. M. Groothuis, Hans de Bont, Erik H.J. Danen, John H. N. Meerman, Marjo de Graauw, Mirjam Luijten, Steven Wink |
|---|---|
| Přispěvatelé: | Nanomedicine & Drug Targeting, Biopharmaceuticals, Discovery, Design and Delivery (BDDD) |
| Rok vydání: | 2014 |
| Předmět: |
TRANSLATION INITIATION
Diclofenac NF-E2-Related Factor 2 Activating transcription factor Apoptosis Pharmacology CHOP Biology Toxicology TOXICITY transcriptomics RNA interference Animals Humans CELL GENE-EXPRESSION INDUCED LIVER-INJURY Tumor Necrosis Factor-alpha ATF6 Gene Expression Profiling Endoplasmic reticulum ATF4 high content microscopy ANTIEPILEPTIC DRUGS NECROSIS-FACTOR-ALPHA Drug Synergism Hep G2 Cells ER STRESS Endoplasmic Reticulum Stress Mice Inbred C57BL Oxidative Stress Carbamazepine Cell killing Hepatocytes Unfolded protein response Cancer research Chemical and Drug Induced Liver Injury Signal transduction INTERNAL-RIBOSOME-ENTRY Transcriptome drug-induced liver injury Genome-Wide Association Study |
| Zdroj: | Toxicological Sciences, 140(1), 144-159 |
| ISSN: | 1096-0929 1096-6080 |
| Popis: | Drug-induced liver injury (DILI) is an important clinical problem. Here, we used a genomics approach to in detail investigate the hypothesis that critical drug-induced toxicity pathways act in synergy with the pro-inflammatory cytokine tumor necrosis factor alpha (TNF alpha) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of 80 DILI compounds in primary human hepatocytes. Compounds displaying weak or no TNF alpha synergism, namely ketoconazole, nefazodone, and methotrexate, failed to synchronously induce both pathways. The ER stress induced was primarily related to protein kinase R-like ER kinase (PERK) and activating transcription factor 4 (ATF4) activation and subsequent expression of C/EBP homologous protein (CHOP), which was all independent of TNF alpha signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision-cut human liver slices. Targeted RNA interference studies revealed that whereas ER stress signaling through inositol-requiring enzyme 1 alpha (IRE1 alpha) and activating transcription factor 6 (ATF6) acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF alpha-induced apoptosis. Whereas inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF alpha cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNF alpha-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing toward caspase-8-dependent TNF alpha-induced apoptosis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|