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

Hittu Matta1, Michael T Eby, Adi F Gazdar

  • 1Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas Texas 75390-8593, USA.

Cancer Biology & Therapy
|March 19, 2003
PubMed

Insights

Mach-related inducer of toxicity (MRIT) or cellular FADD-like IL-1β-converting enzyme inhibitory protein (cFLIP) protects against chemotherapy-induced apoptosis. Downregulating MRITalpha1/cFLIP(L) may overcome multidrug resistance in cancer therapy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Mach-related inducer of toxicity (MRIT)/cellular FADD-like IL-1β-converting enzyme inhibitory protein (cFLIP) is a caspase-8 homolog that inhibits apoptosis.
  • cFLIP(L) is known to protect against death receptor-mediated apoptosis by blocking caspase-8 activation.

Purpose of the Study:

  • To investigate the role of MRITalpha1/cFLIP(L) in chemotherapy-induced apoptosis.
  • To determine if MRITalpha1/cFLIP(L) expression influences sensitivity to various chemotherapeutic agents.

Main Methods:

  • Exogenous expression of MRITalpha1/cFLIP(L) in cancer cell lines.
  • Treatment with diverse chemotherapeutic drugs (doxorubicin, etoposide, cisplatin, etc.).
  • Assessment of apoptosis induction and caspase activation.

Main Results:

  • MRITalpha1/cFLIP(L) conferred protection against apoptosis induced by several chemotherapeutic drugs, but not microtubule-targeting agents like paclitaxel.
  • The protective effect was more pronounced in solid tumor cell lines compared to hematopoietic cell lines.
  • MRITalpha1/cFLIP(L) expression decreased during drug-induced apoptosis, and its exogenous expression delayed caspase-8 and -3 activation.

Conclusions:

  • MRITalpha1/cFLIP(L) plays a significant role in both death receptor- and chemotherapy-induced apoptosis.
  • Downregulation of MRITalpha1/cFLIP(L) could be a strategy to overcome multidrug resistance in cancer therapy.

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