Geserick P, Drewniok C, Hupe M, Haas T L, Diessenbacher P, Sprick M R, Schön M P, Henkler F, Gollnick H, Walczak H, Leverkus M
Department of Dermatology and Venereology, Laboratory for Experimental Dermatology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
Oncogene. 2008 May 15;27(22):3211-20. doi: 10.1038/sj.onc.1210985. Epub 2007 Dec 17.
Death ligands such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and certain forms of CD95L are attractive therapeutic options for metastatic melanoma. Since knowledge about the regulation of death receptor sensitivity in melanoma is sparse, we have analysed these signaling pathways in detail. The loss of CD95 or TRAIL-R1, but not of TRAIL-R2, surface expression correlated with apoptosis sensitivity in a panel of melanoma cell lines. In contrast, the expression of proteins of the apical apoptosis signaling cascade (FADD, initiator caspases-8 and cFLIP) did not predict apoptosis sensitivity. Since both TRAIL-R1 and -R2 transmit apoptotic signals, we asked whether cFLIP, highly expressed in several of the cell lines tested, is sufficient to maintain resistance to TRAIL-R2-mediated apoptosis. Downregulation of cFLIP in TRAIL-R2-positive, TRAIL-resistant IGR cells dramatically increased TRAIL sensitivity. Conversely ectopic expression of cFLIP in TRAIL-sensitive, TRAIL-R2-expressing RPM-EP melanoma cells inhibited TRAIL- and CD95L-mediated cell death. Thus, modulation of cFLIP is sufficient to sensitize TRAIL-R2-expressing cells for TRAIL. Taken together, albeit expressing all proteins necessary for death receptor-mediated apoptosis, TRAIL-R1 negative melanoma cells cannot undergo TRAIL- or CD95L-induced apoptosis due to expression of cFLIP. Hence, cFLIP represents an attractive therapeutic target for melanoma treatment, especially in combination with TRAIL receptor agonists.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）等死亡配体以及某些形式的CD95L是转移性黑色素瘤颇具吸引力的治疗选择。由于关于黑色素瘤中死亡受体敏感性调节的知识匮乏，我们对这些信号通路进行了详细分析。在一组黑色素瘤细胞系中，CD95或TRAIL-R1而非TRAIL-R2的表面表达缺失与凋亡敏感性相关。相比之下，顶端凋亡信号级联反应的蛋白质（FADD、起始半胱天冬酶-8和cFLIP）的表达并不能预测凋亡敏感性。由于TRAIL-R1和TRAIL-R2都能传递凋亡信号，我们探究了在多个测试细胞系中高表达的cFLIP是否足以维持对TRAIL-R2介导的凋亡的抗性。在TRAIL-R2阳性、对TRAIL耐药的IGR细胞中下调cFLIP可显著增加TRAIL敏感性。相反，在对TRAIL敏感、表达TRAIL-R2的RPM-EP黑色素瘤细胞中异位表达cFLIP可抑制TRAIL和CD95L介导的细胞死亡。因此，调节cFLIP足以使表达TRAIL-R2的细胞对TRAIL敏感。综上所述，尽管表达了死亡受体介导的凋亡所需的所有蛋白质，但TRAIL-R1阴性的黑色素瘤细胞由于cFLIP的表达而无法发生TRAIL或CD95L诱导的凋亡。因此，cFLIP是黑色素瘤治疗颇具吸引力的治疗靶点，尤其是与TRAIL受体激动剂联合使用时。
