Nicotine suppresses tunicamycin-induced, but not thapsigargin-induced, expression of GRP78 during ER stress-mediated apoptosis in PC12 cells.
We previously reported that nicotine protected against tunicamycin (Tm)-induced ER stress-mediated apoptosis, but not thapsigargin (Tg)-induced apoptosis in PC12 cells. In the present study, we report that the expression of glucose-regulated protein 78 (GRP78) was suppressed by nicotine in Tm-treated PC12 cells. Interestingly, the GRP78 expression was not changed by nicotine in Tg-treated cells. Moreover, nicotine reduced the activation of caspase-12 in Tm-treated cells, but not in Tg-treated cells. These results suggest that nicotine prevented Tm-induced ER stress-mediated apoptosis by attenuating an early stage of Tm-induced ER stress. It was possible that the suppression of GRP78 expression by nicotine was achieved through the suppression of the Ire1-XBP1 and/or ATF6 pathways. We observed that nicotine suppressed the Tm-induced, but not Tg-induced, splicing of XBP1 mRNA, and also suppressed the Tm-induced, but not Tg-induced, production of cleaved ATF6 in PC12 cells. These results indicate that the suppression of Ire1-XBP1 and ATF6 pathways contributes to the suppression of GRP78 expression by nicotine in Tm-treated PC12 cells, suggesting that nicotine suppresses a common step upstream of both the Ire1-XBP1 and ATF6 pathways which are required for the expression of GRP78 during Tm-induced ER stress.
Sasaya
Harue
H
Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and High Technology Research Center, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan.
Utsumi
Takahiro
T
Shimoke
Koji
K
Nakayama
Hitoshi
H
Matsumura
Yoshinobu
Y
Fukunaga
Kenji
K
Ikeuchi
Toshihiko
T
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000378:metabolism*; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D016716:PC12 Cells; D012326:RNA Splicing / Q000187:drug effects; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D019284:Thapsigargin / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014415:Tunicamycin / Q000037:antagonists & inhibitors*; D000071717:X-Box Binding Protein 1
D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605545:Xbp1 protein, rat; D014415:Tunicamycin; D019284:Thapsigargin; D009538:Nicotine; D020169:Caspases