Caffeoylserotonin Protects Human Keratinocyte HaCaT Cells Against H2 O2 -Induced Oxidative Stress and Apoptosis Through Upregulation of HO-1 Expression via Activation of the PI3K/Akt/Nrf2 Pathway

Phytother Res. 2013 Dec;27(12):1810-8. doi: 10.1002/ptr.4931. Epub 2013 Feb 17.


Caffeoylserotonin (CaS) has strong radical scavenging activity as well as antioxidant activities, protecting cells from lipid peroxidation, intracellular reactive oxygen species generation, DNA damage, and cell death. The molecular mechanism by which CaS protects against oxidative stress is not well understood. Here, we analyzed the cytoprotective activity of CaS in hydrogen peroxide (H2 O2 )-treated keratinocyte HaCaT cells. H2 O2 induced apoptosis in the cells through activation of pro-apoptotic p21, Bax, and caspase-3. Pretreatment with CaS inhibited apoptotic gene expression and activated the anti-apoptotic gene, Bcl-xL. Although CaS did not directly affect heme oxygenase-1 (HO-1) expression, pretreatment with CaS augmented HO-1 expression through an increase in NF-E2-related factor (Nrf2) stability and stimulation of Nrf2 translocation to the nucleus upon H2 O2 exposure. H2 O2 also induced the phosphorylation and subsequent activation of ERK, p38 MAPK, and Akt. Analysis using specific inhibitors of p38 MAPK and Akt demonstrated that only Akt activation was involved in HO-1 and Nrf2 expressions. In addition, PI3K and PKC inhibitors suppressed HO-1/Nrf2 expression and Akt phosphorylation. These results demonstrate that CaS protects against oxidative stress-induced keratinocyte cell death in part through the activation of Nrf2-mediated HO-1 induction via the PI3K/Akt and/or PKC pathways, but not MAPK signaling.

Keywords: Nrf2; antioxidant; caffeoylserotonin; heme oxygenase-1; hydrogen peroxide; keratinocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Caffeic Acids / pharmacology*
  • Cell Line
  • Enzyme Inhibitors / pharmacology
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Keratinocytes / cytology
  • Keratinocytes / drug effects*
  • MAP Kinase Signaling System / drug effects
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress / drug effects*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Serotonin / analogs & derivatives*
  • Serotonin / pharmacology
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Apoptosis Regulatory Proteins
  • Caffeic Acids
  • Enzyme Inhibitors
  • N-caffeoylserotonin
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Serotonin
  • Hydrogen Peroxide
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases