title: Induction of heme oxygenase-1 inhibits cell death in crotonaldehyde-stimulated HepG2 cells via the PKC-δ-p38-Nrf2 pathway.
abstract: BACKGROUND
  Crotonaldehyde, an alpha, beta-unsaturated aldehyde present in cigarette smoke, is an environmental pollutant and a product of lipid peroxidation. It also produces adverse effects to humans and is considered as a risk factor for various diseases. Heme oxygenase-1 (HO-1) plays important roles in protecting cells against oxidative stress as a prime cellular defense mechanism. However, HO-1 may be associated with cell proliferation and resistance to apoptosis in cancer cells. The aim of this study was to examine the effects of HO-1 induction on cell survival in crotonaldehyde-stimulated human hepatocellular carcinoma (HepG2) cells.
  
  
  METHODS
  To investigate the signaling pathway involved in crotonaldehyde-induced HO-1 expression, we compared levels of inhibition efficiency of specific inhibitors and specific small interfering RNAs (siRNAs) of several kinases. The cell-cycle and cell death was measured by FACS and terminal dUTP nick-end labeling (TUNEL) staining.
  
  
  RESULTS
  Treatment with crotonaldehyde caused a significant increase in nuclear translocation of NF-E2 related factor (Nrf2). Treatment with inhibitors of the protein kinase C-δ (PKC-δ) and p38 pathways resulted in obvious blockage of crotonaldehyde-induced HO-1 expression. Furthermore, treatment with HO-1 siRNA and the specific HO-1 inhibitor zinc-protoporphyrin produced an increase in the G(0)/G(1) phase of the cell cycle in crotonaldehyde-stimulated HepG2 cells.
  
  
  CONCLUSIONS
  Taken together, the results support an anti-apoptotic role for HO-1 in crotonaldehyde-stimulated human hepatocellular carcinoma cells and provide a mechanism by which induction of HO-1 expression via PKC-δ-p38 MAPK-Nrf2 pathway may promote tumor resistance to oxidative stress.
authors: Department of Microbiology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Seung Eun
authors: SE
authors: Lee
authors: Hana
authors: H
authors: Yang
authors: Seong Il
authors: SI
authors: Jeong
authors: Young-Ho
authors: YH
authors: Jin
authors: Cheung-Seog
authors: CS
authors: Park
authors: Yong Seek
authors: YS
authors: Park
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000447:Aldehydes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004785:Environmental Pollutants / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D011524:Protoporphyrins / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011524:Protoporphyrins; D034741:RNA, Small Interfering; C017803:zinc protoporphyrin; C012796:2-butenal; D051547:Heme Oxygenase-1; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases