Cellular FLICE-like inhibitory protein (c-FLIP): A novel target for Taxol-induced apoptosis

• Published in: Biochemical pharmacology 2006-05, Vol.71 (11), p.1551-1561
• Main Authors: Day, Travis W., Najafi, Farhad, Wu, Ching-Huang, Safa, Ahmad R.
• Format: Article
• Language: English
• Subjects: Ageing, cell death; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; C-FLIP; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 10; Caspase 8; Caspases - metabolism; Cell Line, Tumor; Cell physiology; Death receptors; Dose-Response Relationship, Drug; Down-Regulation; Fundamental and applied biological sciences. Psychology; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - physiology; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - pathology; Molecular and cellular biology; Paclitaxel - pharmacology; Taxol
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2006.02.015

It is known that by binding to the FAS-associated death domain (FADD) protein and/or caspases-8 and -10 at the level of the death-inducing signaling complex (DISC), cellular FLICE-like inhibitory protein (c-FLIP) can prevent apoptosis triggered by death-inducing ligands. We investigated whether the c-FLIP splice variants, c-FLIP long [c-FLIP(L)] and c-FLIP short [c-FLIP(S)], play a role in Taxol-induced apoptosis. Our results showed that low Taxol concentrations triggered caspase-8- and caspase-10-dependent apoptosis in the CCRF-HSB-2 human lymphoblastic leukemia cell line, and induced the down-regulation of c-FLIP(S) and c-FLIP(L). Taxol decreased the expression of c-FLIP by a post-transcriptional and caspase-independent mechanism. To explore the distinct functions of the c-FLIP variants in Taxol-induced apoptosis, we transfected the cells with expression vectors carrying c-FLIP(L) and c-FLIP(S) in the sense orientation or c-FLIP(S) in the antisense orientation [c-FLIP(S)-AS]. Caspases-8 and -10 were more efficiently activated in the c-FLIP(S)-AS strain treated with 5–50 nM Taxol, which revealed that c-FLIP regulates Taxol-induced apoptosis by interacting with these caspases. Furthermore, our data showed that increased expression of c-FLIP(L) or c-FLIP(S) reduced apoptosis at 5–50 nM Taxol concentrations suggesting that both isoforms of c-FLIP prevent Taxol-induced apoptosis. These results revealed that Taxol induces apoptosis by down-regulating c-FLIP(S) and c-FLIP(L) expression.