Low-dose UV-radiation sensitizes keratinocytes to TRAIL-induced apoptosis

J Cell Physiol. 2004 Jul;200(1):155-66. doi: 10.1002/jcp.20017.


The impact of low-dose ultraviolet light (UV-light) on apoptotic susceptibility of keratinocytes (KCs) induced by TRAIL is unclear. Skin expresses a functional form of TRAIL, and while sun exposure influences TRAIL death receptors, a role for decoy receptors has not been evaluated. Unraveling mechanisms involving apoptotic sensitivity of KCs is important because skin is the first target of UV-light, and a site for commonly occurring cancers. Since apoptosis is a homeostatic process eliminating UV-light induced DNA damaged cells, elucidating molecular events regulating apoptosis enhances understanding of cutaneous photocarcinogenesis. Here we demonstrate low-dose UV-light enhances susceptibility of KCs to TRAIL-induced apoptosis. Low-dose UV-light selectively reduces decoy receptors, without influencing death receptor levels. UV-induced enhanced apoptotic susceptibility was reduced by over-expression of decoy receptor TRAIL-R4, but not TRAIL-R3; or treatment with thiol compound pyrrolidine dithiocarbamate (PDTC), which also enhanced TRAIL-R4 levels. Besides influencing decoy receptors, low-dose UV-light plus TRAIL also synergistically promoted cytochrome c and Smac release from mitochondria. Inhibitors directed against caspases 2, 3, 8, and 9 reduced the synergistic apoptotic response following low-dose UV-light plus TRAIL exposure; as did forced over-expression of Bcl-x and dominant negative (DN) constructs of FADD and caspase 9. Thus, relative levels of decoy receptors significantly influence susceptibility of KCs to TRAIL-induced apoptosis with concomitant low-dose UV-light exposure; in addition to the apoptotic pathway mediated by mitochondrial permeabilization.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Blotting, Western
  • Carrier Proteins / metabolism
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cells, Cultured
  • Cytochromes c / metabolism
  • Fluorescent Antibody Technique, Indirect
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • Keratinocytes / radiation effects*
  • Luciferases / genetics
  • Male
  • Membrane Glycoproteins / metabolism*
  • Mitochondria / metabolism
  • Mitochondria / radiation effects
  • Mitochondrial Proteins / metabolism
  • Penis / anatomy & histology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / metabolism
  • Retroviridae / genetics
  • Skin / cytology
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Suppressor Protein p53 / metabolism
  • Ultraviolet Rays
  • bcl-X Protein


  • Apoptosis Regulatory Proteins
  • BCL2L1 protein, human
  • Carrier Proteins
  • Caspase Inhibitors
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Mitochondrial Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • Cytochromes c
  • Luciferases
  • Caspases