Department of Dermatology and Allergy, Skin Cancer Center, Charité—Universitätsmedizin Berlin, Berlin, Germany

Correspondence: Jürgen Eberle, PhD, Department of Dermatology and Allergy, Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, Fabeckstrasse 60-62, 14195 Berlin, Germany. Email: juergen.eberle@charite.de

Received 10 February 2005; Revised 31 May 2005; Accepted 18 June 2005; Published online 25 October 2005.

Abstract

Therapy resistance is crucial for the high mortality of melanoma. The death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) bears high potential as a new anticancer agent, as binding to the death receptors TRAIL receptor 1/death receptor 4 (TRAIL-R1/DR4) or TRAIL receptor 2/death receptor 5 (TRAIL-R2/DR5) triggers apoptosis in most cancer cells. For melanoma, however, only a weak responsiveness of primary cultures was reported, and in particular the role of DR4 was neglected. For evaluating melanoma susceptibility, we studied the functionality of DR4 and DR5 in melanoma cells as well as their expression in vivo. DR5 was consistently expressed in melanoma cell lines, whereas DR4 was found in only 2/7 cell lines. High sensitivity to TRAIL-induced apoptosis was characteristic for DR4-positive melanoma cells, whereas DR4-negative cells showed less and delayed response or were resistant. The use of selective DR4/DR5 blocking antibodies unequivocally proved the prevalent role of DR4 in those melanoma cells, where it was expressed. The significance of these data for the in vivo situation was finally evaluated by immunohistochemistry, which proved pronounced expression of DR4 as well as of DR5 in melanoma primary tumors. Thus, DR4 expression in vivo and the high efficiency of DR4-mediated apoptosis may suggest reassessment of the suitability of TRAIL and especially of DR4-based strategies for melanoma treatment.