Role of MRIT/cFLIP in protection against chemotherapy-induced apoptosis

Cancer Biol Ther. Nov-Dec 2002;1(6):652-60. doi: 10.4161/cbt.315.

Abstract

MRIT (Mach-related inducer of toxicity)/cFLIP (cellular FADD like interlukin1-beta converting enzyme inhibitory protein) is a proteolytically inactive structural homologue of caspase-8, which is known to protect against death receptors-induced apoptosis by blocking the activation of caspase-8. We have observed that exogenous expression of MRITalpha1/cFLIP(L) isoform also protects against cell death induced by a diverse group of chemotherapeutic drugs with different mechanisms of action, including doxorubicin, etoposide, cytosine arabinoside, daunorubicin, chlorambucil and cisplatin. However, MRITalpha1/cFLIP(L) failed to protect against apoptosis induced by paclitaxel and vincristine, two microtubule-damaging agents. Although MRITalpha1/cFLIP(L) protects against chemotherapy-induced apoptosis in both solid tumor and hematopoietic cell lines, this effect was more pronounced in the former. MRITalpha1/cFLIP(L) expression is decreased during drug-induced apoptosis and exogenous expression of MRITalpha1/cFLIP(L) delays the activation of caspase-8 and -3 during drug- induced apoptosis. These results suggest that MRITalpha1/cFLIPL may be an important determinant of both death receptor- and chemotherapy-induced apoptosis and strategies aimed at downregulating its expression deserve further study as a way to overcome multidrug resistance to cancer therapy.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / physiology*
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Cytoprotection / drug effects
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression / drug effects*
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Neoplasms / pathology
  • Neoplasms / prevention & control*
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases