In the Huh7 Hepatoma Cells Diclofenac and Indomethacin Activate Differently the Unfolded Protein Response and Induce ER Stress Apoptosis



Silvia Franceschelli, Ornella Moltedo, Giuseppina Amodio, Gianfranco Tajana, Paolo Remondelli*
Dipartimento di Scienze Farmaceutiche e Biomediche, University of Salerno, via Ponte Don Melillo, I-84084, Fisciano-Salerno, Italy


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© Franceschelli et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http: //creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Dipartimento di Scienze Farmaceutiche e Biomediche, Università degli Studi di Salerno, via Ponte Don Melillo, I-84084, Fisciano-Salerno, Italy; Tel: +39-089-969767; Fax: +39-089-969602; E-mail: premondelli@unisa.it


Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are cyclooxygenases (COXs) inhibitors frequently used in the treatment of acute and chronic inflammation. Side effects of NSAIDs are often due to their ability to induce apoptosis. Located at the Endoplasmic Reticulum membranes a tripartite signalling pathway, collectively known as the Unfolded Protein Response (UPR), decides survival or death of cells exposed to cytotoxic agents. To shed light on the molecular events responsible for the cytotoxicity of NSAIDs, we analysed the ability of diclofenac and indomethacin to activate the UPR in the human hepatoma cell line Huh7. We report that both NSAIDs can induce differently the single arms of the UPR. We show that indomethacin turns on the PERK and, only in part, the ATF6 and IRE1 pathways. Instead, diclofenac reduces the expression of ATF6 and does not stimulate the IRE1 endonuclease, which drives the expression of the prosurvival factor XBP1. Diclofenac, as well as indomethacin, is able to activate efficiently only the PERK pathway of the UPR, which induces the expression of the proapoptotic GADD153/CHOP protein. Our results highlight the importance of the UPR in evaluating the potential of drugs to induce apoptosis.

Keywords: ER Stress, UPR, PERK, IRE1, ATF6α, NSAID, diclofenac, indomethacin, apoptosis.