Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg and Department of Immune Control, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany.
Cell Death Dis. 2011 Dec 22;2(12):e245. doi: 10.1038/cddis.2011.131.
Deregulation of apoptosis is common in cancer and is often caused by overexpression of anti-apoptotic proteins in tumour cells. One important regulator of apoptosis is the cellular FLICE-inhibitory protein (c-FLIP), which is overexpressed, for example, in melanoma and Hodgkin's lymphoma cells. Here, we addressed the question whether deregulated c-FLIP expression in urothelial carcinoma impinges on the ability of death ligands to induce apoptosis. In particular, we investigated the role of the c-FLIP splice variants c-FLIP(long) (c-FLIP(L)) and c-FLIP(short) (c-FLIP(S)), which can have opposing functions. We observed diminished expression of the c-FLIP(L) isoform in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells, whereas c-FLIP(S) was unchanged. Overexpression and RNA interference studies in urothelial cell lines nevertheless demonstrated that c-FLIP remained a crucial factor conferring resistance towards induction of apoptosis by death ligands CD95L and TRAIL. Isoform-specific RNA interference showed c-FLIP(L) to be of particular importance. Thus, urothelial carcinoma cells appear to fine-tune c-FLIP expression to a level sufficient for protection against activation of apoptosis by the extrinsic pathway. Therefore, targeting c-FLIP, and especially the c-FLIP(L) isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours.
细胞凋亡的失调在癌症中很常见，通常是由于肿瘤细胞中抗凋亡蛋白的过度表达引起的。细胞凋亡的一个重要调节因子是细胞 FLICE 抑制蛋白（c-FLIP），例如在黑色素瘤和霍奇金淋巴瘤细胞中过度表达。在这里，我们研究了尿路上皮癌中失调的 c-FLIP 表达是否影响死亡配体诱导细胞凋亡的能力。特别是，我们研究了 c-FLIP 剪接变体 c-FLIP(long)（c-FLIP(L)）和 c-FLIP(short)（c-FLIP(S)）的作用，它们可能具有相反的功能。我们观察到与正常尿路上皮组织和细胞相比，尿路上皮癌组织和已建立的癌细胞系中 c-FLIP(L) 同工型的表达减少，而 c-FLIP(S) 没有改变。然而，在尿路上皮细胞系中的过表达和 RNA 干扰研究表明，c-FLIP 仍然是赋予对死亡配体 CD95L 和 TRAIL 诱导细胞凋亡的抗性的关键因素。同工型特异性 RNA 干扰表明 c-FLIP(L) 尤为重要。因此，尿路上皮癌细胞似乎将 c-FLIP 表达精细调节到足以防止外源性途径激活细胞凋亡的水平。因此，针对 c-FLIP，特别是 c-FLIP(L) 同工型，可能有助于在其他耐药肿瘤中基于细胞凋亡的膀胱癌治疗。
