Activation of HSP90/HSF1 Signaling as an Adaptive Response to an Electrophilic Metabolite of Morphine

Morphinone (MO) is an electrophilic metabolite of morphine that covalently binds to protein thiols, resulting in toxicity in vitro and in vivo. We have previously identified a variety of redox signaling pathways that are activated during electrophilic stress. However, the role of MO in such activati...

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 2023/02/01, Vol.46(2), pp.334-337
Main Authors: Matsuo, Kohei, Abiko, Yumi, Yamano, Shigeru, Matsusue, Kimihiko, Kumagai, Yoshito
Format: Article
Language:English
Subjects:
B-cell lymphoma
Biotin
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
electrophile
heat shock factor 1
Heat shock factors
heat shock protein
Heat shock proteins
Heat Shock Transcription Factors - genetics
Hep G2 Cells
HSF1 protein
HSP70 Heat-Shock Proteins - genetics
HSP90 Heat-Shock Proteins
Hsp90 protein
Humans
Lymphocytes B
Metabolites
Morphine
Morphine - pharmacology
morphinone
Nuclear transport
Protein thiols
redox signaling
Signal transduction
Thiols
Toxicity
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary:Morphinone (MO) is an electrophilic metabolite of morphine that covalently binds to protein thiols, resulting in toxicity in vitro and in vivo. We have previously identified a variety of redox signaling pathways that are activated during electrophilic stress. However, the role of MO in such activation remains unknown. In this study, we examined whether MO could activate heat shock protein (HSP) 90/heat shock factor (HSF) 1 signaling in HepG2 cells. MO exposure caused S-modification of HSP90 (determined using biotin-PEAC5-maleimide labeling) and nuclear translocation of transcription factor HSF1, thereby up-regulating its downstream genes encoding B-cell lymphoma 2-associated anthanogene 3 and heat shock 70 kDa protein 1. However, dihydromorphinone, a non-electrophilic metabolite of morphine, had little effect on HSF1 activation or upregulation of these genes, suggesting that covalent modification plays a role in this process and that the HSP90/HSF1 pathway is a redox-signaled adaptive response to morphine metabolism.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.b22-00531