N-acetyl cysteine and penicillamine induce apoptosis via the ER stress response-signaling pathway

Mol Carcinog. 2010 Jan;49(1):68-74. doi: 10.1002/mc.20578.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology*
  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Activating Transcription Factor 6 / genetics
  • Activating Transcription Factor 6 / metabolism
  • Apoptosis / drug effects*
  • Blotting, Western
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Chaperone BiP
  • Flow Cytometry
  • HeLa Cells
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Penicillamine / pharmacology*
  • RNA Interference
  • Regulatory Factor X Transcription Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • X-Box Binding Protein 1
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism


  • ATF4 protein, human
  • ATF6 protein, human
  • Activating Transcription Factor 6
  • DDIT3 protein, human
  • DNA-Binding Proteins
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • PERK kinase
  • eIF-2 Kinase
  • Penicillamine
  • Acetylcysteine