Resistance of human melanoma cells against the death ligand TRAIL is reversed by ultraviolet-B radiation via downregulation of FLIP

J Invest Dermatol. 2004 Oct;123(4):746-54. doi: 10.1111/j.0022-202X.2004.23420.x.

Abstract

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a potential anticancer drug since it induces apoptosis preferentially in malignant but not in normal cells. Not all cancer cells, however, are TRAIL susceptible. Chemotherapeutic drugs and ionizing radiation have been found to be able to sensitize resistant tumor cells for TRAIL-induced apoptosis. Since ultraviolet B radiation (UVB) is a potent inducer of apoptosis but exhibits much less adverse effects, we studied whether UVB sensitizes TRAIL-resistant melanoma cells. Therefore, we analyzed the TRAIL-sensitive human cell line A-375 in comparison to the resistant cell line IGR-37. Both cell lines showed expression of the long form of the antiapoptotic FLICE inhibitory protein FLIP(L) which, however, was partially cleaved into the 43 kDa form in A-375 cells. In addition, only IGR-37 cells expressed the short splicing variant FLIP(S), which exerts high antiapoptotic activity. Accordingly, transient overexpression of FLIP(S) rendered A-375 cells resistant to TRAIL. Upon exposure to low UVB doses, TRAIL-treated IGR-37 cells underwent pronounced apoptosis and TRAIL sensitivity of A-375 cells was dramatically increased. In both cases, UVB caused an inhibition of flip expression. This study indicates that (i) the expression level and the processing status of FLIP may play a crucial role in determining the sensitivity of melanoma cells towards TRAIL and (ii) expression of FLIP is regulated by UVB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 8
  • Caspase Inhibitors
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / radiation effects
  • Dose-Response Relationship, Drug
  • Down-Regulation / radiation effects
  • Drug Resistance, Neoplasm / radiation effects
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Melanocytes / cytology
  • Melanocytes / metabolism
  • Melanocytes / radiation effects
  • Melanoma*
  • Membrane Glycoproteins / pharmacology*
  • Skin Neoplasms*
  • TNF-Related Apoptosis-Inducing Ligand
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Ultraviolet Rays

Substances

  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Caspase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • CASP8 protein, human
  • Caspase 8