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: Seung Eun Lee, Hana Yang, Seong Il Jeong, Young-Ho Jin, Cheung-Seog Park, Yong Seek Park
• Journal: PloS one (PLoS One) Vol. 7 Issue 7 Pg. e41676 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22848562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aldehydes
• Environmental Pollutants
• Enzyme Inhibitors
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Protoporphyrins
• RNA, Small Interfering
• zinc protoporphyrin
• 2-butenal
• Heme Oxygenase-1
• Protein Kinase C-delta
• p38 Mitogen-Activated Protein Kinases

Topics

• Active Transport, Cell Nucleus (drug effects)
• Aldehydes (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Nucleus (drug effects, metabolism)
• Cell Survival (drug effects)
• Environmental Pollutants (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Gene Knockdown Techniques
• Heme Oxygenase-1 (antagonists & inhibitors, deficiency, genetics)
• Hep G2 Cells
• Humans
• NF-E2-Related Factor 2 (metabolism)
• Protein Kinase C-delta (metabolism)
• Protoporphyrins (pharmacology)
• RNA, Small Interfering (genetics)
• Signal Transduction (drug effects)
• Transcriptional Activation (drug effects)
• p38 Mitogen-Activated Protein Kinases (metabolism)