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

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/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, MRITα1/cFLIP_L failed to protect against apoptosis induced by paclitaxel and vincristine, two microtubule-damaging agents. Although MRITα1/cFLIP_L protects against chemotherapy-induced apoptosis in both solid tumor and hematopoietic cell lines, this effect was more pronounced in the former. MRITα1/cFLIP_L expression is decreased during drug-induced apoptosis and exogenous expression of MRITα1/cFLIP_L 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.