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

Hittu Matta, Michael T. Eby, Adi F. Gazdar, Preet M. Chaudhary

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

MRIT (Mach-related inducer of toxicity)/cFLIP (cellular FADD like interleukin1-β 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 MRITα1/cFLIPL 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, MRITα1/cFLIPL failed to protect against apoptosis induced by paclitaxel and vincristine, two microtubule-damaging agents. Although MRITα1/cFLIPL protects against chemotherapy-induced apoptosis in both solid tumor and hematopoietic cell lines, this effect was more pronounced in the former. MRITα1/cFLIPL expression is decreased during drug-induced apoptosis and exogenous expression of MRITα1/cFLIPL delays the activation of caspase-8 and -3 during drug-induced apoptosis. These results suggest that MRITα1/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.

Original languageEnglish (US)
Pages (from-to)652-660
Number of pages9
JournalCancer Biology and Therapy
Volume1
Issue number6
DOIs
StatePublished - 2002

Keywords

  • Apoptosis
  • Caspase
  • Chemotherapy
  • Drug-resistance
  • MRIT
  • c-FLIP

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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