Caffeic acid phenethylester increases stress resistance and enhances lifespan in Caenorhabditis elegans by modulation of the insulin-like DAF-16 signalling pathway

PLoS One. 2014 Jun 25;9(6):e100256. doi: 10.1371/journal.pone.0100256. eCollection 2014.

Abstract

CAPE is an active constituent of propolis which is widely used in traditional medicine. This hydroxycinnamic acid derivate is a known activator of the redox-active Nrf2 signalling pathway in mammalian cells. We used C. elegans to investigate the effects of this compound on accumulation of reactive oxygen species and the modulation of the pivotal redox-active pathways SKN-1 and DAF-16 (homologues of Nrf2 and FoxO, respectively) in this model organism; these results were compared to the effects in Hct116 human colon carcinoma cells. CAPE exerts a strong antioxidative effect in C. elegans: The increase of reactive oxygen species induced by thermal stress was diminished by about 50%. CAPE caused a nuclear translocation of DAF-16, but not SKN-1. CAPE increased stress resistance of the nematode against thermal stress and finally a prolongation of the median and maximum lifespan by 9 and 17%, respectively. This increase in stress resistance and lifespan was dependent on DAF-16 as shown in experiments using a DAF-16 loss of function mutant strain. Life prolongation was retained under SKN-1 RNAi conditions showing that the effect is SKN-1 independent. The results of CAPE obtained in C. elegans differed from the results obtained in Hct116 colon carcinoma cells: CAPE also caused strong antioxidative effects in the mammalian cells, but no activation of the FoxO4 signalling pathway was detectable. Instead, an activation of the Nrf2 signalling pathway was shown by luciferase assay and western blots.

Conclusion: CAPE activates the insulin-like DAF-16, but not the SKN-1 signalling pathway in C. elegans and therefore enhances the stress resistance and lifespan of this organism. Since modulation of the DAF-16 pathway was found to be a pivotal effect of CAPE in C. elegans, this has to be taken into account for the investigation of the molecular mechanisms of the traditional use of propolis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Caenorhabditis elegans / cytology*
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism*
  • Caffeic Acids / pharmacology*
  • DNA-Binding Proteins / metabolism
  • Forkhead Transcription Factors
  • HCT116 Cells
  • Humans
  • Insulin / metabolism
  • Longevity / drug effects*
  • Phenylethyl Alcohol / analogs & derivatives*
  • Phenylethyl Alcohol / pharmacology
  • Signal Transduction / drug effects*
  • Stress, Physiological / drug effects*
  • Temperature
  • Transcription Factors / metabolism*

Substances

  • Antioxidants
  • Caenorhabditis elegans Proteins
  • Caffeic Acids
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Insulin
  • Transcription Factors
  • daf-16 protein, C elegans
  • skn-1 protein, C elegans
  • caffeic acid phenethyl ester
  • Phenylethyl Alcohol

Grants and funding

Funding provided by the "Deutsche Forschungsgemeinschaft" (DFG - research training group 1427 “Food constituents as triggers of nuclear receptor mediated intestinal signalling”). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.