1. ^*Department of Dermatology, University Münster, Münster, Germany
2. ^†Department of Dermatology, University Kiel, Kiel, Germany

Correspondence: Dagmar Kulms, PhD, Laboratory of Cell Biology, Department of Dermatology, University of Münster, Von-Esmarch-Strasse 58, D-48149 Münster, Germany. Email: dkulms@uni-muenster.de

Received 23 October 2003; Revised 5 May 2004; Accepted 14 May 2004; Published online 10 September 2004.

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.