N-acetyl cysteine and penicillamine induce apoptosis via the ER stress response-signaling pathway.
N-acetyl cysteine (NAC) and penicillamine (PEN) have been shown to induce apoptosis in multiple types of human cancer cells; however, the molecular mechanism underlying this activity is unclear. This study was designed to identify the genes responsible for apoptosis induction by NAC and PEN. We found that glucose-regulated protein 78 (GRP78) was upregulated in HeLa cells following treatment with NAC or PEN. GRP78 is a central regulator of endoplasmic reticulum (ER) stress and has been used as a marker of ER stress. Additionally, both the activating transcription factor 6 (ATF6) protein and X box-binding protein 1 (XBP1) mRNA were processed, which facilitates the expression of C/EBP homologous protein (CHOP), a key-signaling component of ER stress-induced apoptosis. Furthermore, the PERK-ATF4 pathway, which also induces the expression of CHOP, was activated in NAC-treated cells. The role of the ER stress pathway was further confirmed through the small interfering RNA (siRNA)-mediated knockdown of CHOP, which attenuated NAC and PEN-induced apoptosis. These results demonstrate that NAC- and PEN-induced apoptosis in HeLa cells is mediated by the ER stress pathway.
Guan
Dongyin
D
Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China.
Xu
Yingying
Y
Yang
Min
M
Wang
Hao
H
Wang
Xiaoming
X
Shen
Zonghou
Z
D000111:Acetylcysteine / Q000494:pharmacology*; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005434:Flow Cytometry; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010396:Penicillamine / Q000494:pharmacology*; D034622:RNA Interference; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D000111:Acetylcysteine; D051701:Activating Transcription Factor 4; D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D010396:Penicillamine; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C497109:ATF4 protein, human; C497111:ATF6 protein, human; C497249:DDIT3 protein, human; C000717247:HSPA5 protein, human; C000605543:XBP1 protein, human