title: Lidocaine induces endoplasmic reticulum stress-associated apoptosis in vitro and in vivo.
abstract: We demonstrated that upregulation of both gene expression of endoplasmic reticulum (ER) stress chaperones (BiP, calnexin, calreticulin, and PDI) and ER stress sensors (ATF6, IRE1 and PERK) was induced by lidocaine, a local anesthetic, in PC12 cells. In addition to gene regulation, lidocaine also induced typical ER stress phenomena such as ART6 proteolytic cleavage, eIF2 alpha phosphorylation, and XBP1 mRNA splicing. In in vivo experiments, while lidocaine downregulated gene expression of antiapoptotic factors (Bcl-2 and Bcl-xl), pro-apoptotic factor (Bak and Bax) gene expression was upregulated. Furthermore, lidocaine induced apoptosis, as measured histochemically, and upregulated PARP1, a DNA damage repair enzyme. These results are the first to show that lidocaine induces apoptosis through ER stress in vitro and in vivo.
authors.affiliation: Department of Emergency Medicine, Konkuk University Medical Center, Seoul 143-729, Korea; E-Mails:  sean1011@daum.net  (D.Y.H.);  lkrer@kuh.ac.kr  (K.R.L.).
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hong
authors.forename: Kisang
authors.initials: K
authors.lastname: Kwon
authors.forename: Kyeong Ryong
authors.initials: KR
authors.lastname: Lee
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Goo
authors.forename: Kweon
authors.initials: K
authors.lastname: Yu
authors.forename: Seung-Whan
authors.initials: SW
authors.lastname: Kim
authors.forename: O-Yu
authors.initials: OY
authors.lastname: Kwon
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D037281:Calnexin / Q000235:genetics / Q000378:metabolism; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051702:Activating Transcription Factor 6; D037281:Calnexin; D037282:Calreticulin; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D008012:Lidocaine; D008565:Membrane Proteins; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019892:eIF-2 Kinase; C497113:Atf6 protein, rat; C494774:Bak1 protein, rat; C494828:Bax protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C000605545:Xbp1 protein, rat; C499322:Parp1 protein, rat; C486557:Ern2 protein, rat