Role of MRIT/cFLIP in Protection Against Chemotherapy-Induced Apoptosis

MRIT (Mach-related inducer of toxicity)/cFLIP (cellular FADD like interlukin1-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...

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Bibliographic Details
Published in:Cancer biology & therapy 2002-11, Vol.1 (6), p.646-654
Main Authors: Adi F. Gazdar, Preet M. Chaudhary, Michael T. Eby, Hittu Matta
Format: Article
Language:English
Subjects:
Binding
Biology
Bioscience
Calcium
Cancer
Cell
Cycle
Landes
Organogenesis
Proteins
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Summary:MRIT (Mach-related inducer of toxicity)/cFLIP (cellular FADD like interlukin1-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.
ISSN:1538-4047
1555-8576