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

By Silvia Franceschelli, Ornella Moltedo, Giuseppina Amodio, Gianfranco Tajana and Paolo Remondelli


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

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Publisher: Bentham Open
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  1. (2001). A novel ER alpha-mannosidaselike prorein accelerates ER-associated degradation. EMBO Rep.,
  2. (1991). A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry.
  3. (2001). Activation of JNK and transcriptional repressor ATF3/LRF1 through the IRE1/TRAF2 pathway is implicated in human vascular endothelial cell death by homocysteine.
  4. (2000). ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response.
  5. (2009). Cellular responses to endoplasmic reticulum stress and apoptosis. Apoptosis,
  6. (1998). Chop is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev.,
  7. (2002). Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett.,
  8. (2003). Diclofenac induces apoptosis in hepatocytes. Toxicol. In Vitro,
  9. (2002). Disparate effects of non-steroidal antiinflammatory drugs on apoptosis in guinea-pig gastric mucous cells:inhibition of basal apoptosis by
  10. (2000). Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response.
  11. (1996). Effects of nonsteroidal antiinflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway.
  12. (2003). Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation.
  13. (2004). Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. Cell Death Differ.,
  14. (2002). ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals.
  15. (2005). ER stress signaling by regulated proteolysis of ATF6. Methods,
  16. (1997). Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal antiinflammatory drug: independence from COX-2 protein expression. Clin. Cancer Res.,
  17. (2003). Induction of GADD153 and Bak: novel molecular targets of fenretinide-induced apoptosis of neutoblastoma. Cancer Lett.,
  18. (2001). Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals.
  19. (2006). Nitric oxide-induced endoplasmic reticulum stress activates the expression of cargo receptor proteins and alters the glycoprotein transport to the Golgi complex.
  20. (2001). Non steroidal anti-inflammatory drugs induce apoptosis in gastric cancer cells through up-regulation of bax and bak. Carcinogenesis,
  21. (1996). Nonsteroidal antiinflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: effects on cell cycle and apoptosis.
  22. (2003). NSAIDs caused gastric mucosal injury: with a special reference to COX-2.
  23. (2001). NSAIDs induce both necrosis and apoptosis in guinea pig gastric mucosal cells in primary culture.
  24. (2001). Organelle-specific initiation of cell death pathways.
  25. (2000). Perk is essential for translational regulation and cell survival during the unfolded protein response.
  26. (2009). Preventing oxidative stress: a new role for XBP1. Cell Death Differ.,
  27. (1997). Prostaglandin H synthases, nonsteroidal antiinflammatory drugs, and colon cancer.
  28. (2002). Role of mitochondrial transition in diclofenac-induced hepatocyte injury in rats. Hepatology,
  29. (2004). Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ.,
  30. (1999). Signal transduction by the c-Jun N-terminal kinase.
  31. signaling affects cell fate during the unfolded protein response. Science,
  32. (1999). Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev.,
  33. (2011). The chemopreventive agent N(4-hydroxyphenyl)retinamide induces apoptosis through a
  34. (2005). The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Method,
  35. (2002). Transcriptional and translational control in the Mammalian unfolded protein response.
  36. (2003). XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response.
  37. (2004). XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res.,