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

Biochem Pharmacol. 2006 May 28;71(11):1551-61. doi: 10.1016/j.bcp.2006.02.015. Epub 2006 Mar 31.


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 5-50nM 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 5-50nM 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Caspase 10
  • Caspase 8
  • Caspases / metabolism
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • 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
  • Paclitaxel / pharmacology*


  • Antineoplastic Agents, Phytogenic
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Intracellular Signaling Peptides and Proteins
  • CASP8 protein, human
  • Caspase 10
  • Caspase 8
  • Caspases
  • CASP10 protein, human
  • Paclitaxel