TY - JOUR
T1 - Indomethacin and ibuprofen induce Hsc70 nuclear localization and activation of the heat shock response in HeLa cells
AU - Lagunas, Lucio
AU - Bradbury, C. Matthew
AU - Laszlo, Andrei
AU - Hunt, Clayton R.
AU - Gius, David
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2004/1/23
Y1 - 2004/1/23
N2 - It has been established that non-steroidal anti-inflammatory drugs (NSAIDs), such as sodium salicylate, sulindac, ibuprofen, and indomethacin, induce anti-inflammatory and anti-proliferative effects independent of cyclooxygenase. These cyclooxygenase-independent pharmacodynamic effects appear to regulate several signaling pathways involving proliferation, apoptosis, and heat shock response. However, the mechanisms of these actions remain an area of ongoing investigation. Hsc70 is a cytoplasmic chaperone protein involved in folding and trafficking of client proteins to different subcellular compartments, plays roles in signal transduction and apoptosis processes, and translocates to the nucleus following exposure to heat shock. Since NSAIDs induce some aspects of the heat shock response, we hypothesized that they may also induce Hsc70 nuclear translocation. Western immunoblotting and indirect cellular immunofluorescence showed that indomethacin and ibuprofen induce Hsc70 nuclear translocation at concentrations previously shown to induce HSF DNA-binding activity. Chemical inhibition of both p38MAPK and Erk42/44 had no effect on localization patterns. In addition, while indomethacin has been shown to behave as an oxidative stressor, the radical scavenging agent, N-acetyl cysteine, did not inhibit nuclear translocation. These results indicate that induction of the heat shock response by NSAIDs occurs at concentrations fivefold greater than those required to inhibit cyclooxygenase activity, suggesting a cyclooxygenase-independent mechanism, and in the presence or absence of kinase inhibitors and a free radical scavenger, suggesting independence of Erk42/44 or p38MAPK activities and intracellular oxidoreductive state.
AB - It has been established that non-steroidal anti-inflammatory drugs (NSAIDs), such as sodium salicylate, sulindac, ibuprofen, and indomethacin, induce anti-inflammatory and anti-proliferative effects independent of cyclooxygenase. These cyclooxygenase-independent pharmacodynamic effects appear to regulate several signaling pathways involving proliferation, apoptosis, and heat shock response. However, the mechanisms of these actions remain an area of ongoing investigation. Hsc70 is a cytoplasmic chaperone protein involved in folding and trafficking of client proteins to different subcellular compartments, plays roles in signal transduction and apoptosis processes, and translocates to the nucleus following exposure to heat shock. Since NSAIDs induce some aspects of the heat shock response, we hypothesized that they may also induce Hsc70 nuclear translocation. Western immunoblotting and indirect cellular immunofluorescence showed that indomethacin and ibuprofen induce Hsc70 nuclear translocation at concentrations previously shown to induce HSF DNA-binding activity. Chemical inhibition of both p38MAPK and Erk42/44 had no effect on localization patterns. In addition, while indomethacin has been shown to behave as an oxidative stressor, the radical scavenging agent, N-acetyl cysteine, did not inhibit nuclear translocation. These results indicate that induction of the heat shock response by NSAIDs occurs at concentrations fivefold greater than those required to inhibit cyclooxygenase activity, suggesting a cyclooxygenase-independent mechanism, and in the presence or absence of kinase inhibitors and a free radical scavenger, suggesting independence of Erk42/44 or p38MAPK activities and intracellular oxidoreductive state.
KW - Hsc70
KW - Ibuprofen
KW - Indomethacin
KW - Nuclear localization
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U2 - 10.1016/j.bbrc.2003.12.018
DO - 10.1016/j.bbrc.2003.12.018
M3 - Article
C2 - 14706622
AN - SCOPUS:0346728756
SN - 0006-291X
VL - 313
SP - 863
EP - 870
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -