Matta Hittu, Eby Michael T, Gazdar Adi F, Chaudhary Preet M
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas Texas 75390-8593, USA.
Cancer Biol Ther. 2002 Nov-Dec;1(6):652-60. doi: 10.4161/cbt.315.
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.
MRIT（与机器相关的毒性诱导物）/cFLIP（细胞FADD样白细胞介素1-β转化酶抑制蛋白）是半胱天冬酶-8的蛋白水解无活性结构同源物，已知其通过阻断半胱天冬酶-8的激活来防止死亡受体诱导的细胞凋亡。我们观察到，MRITα1/cFLIP（L）异构体的外源性表达也能防止由多种具有不同作用机制的化疗药物诱导的细胞死亡，这些药物包括阿霉素、依托泊苷、阿糖胞苷、柔红霉素、苯丁酸氮芥和顺铂。然而，MRITα1/cFLIP（L）未能防止由紫杉醇和长春新碱这两种微管损伤剂诱导的细胞凋亡。尽管MRITα1/cFLIP（L）在实体瘤和造血细胞系中均能防止化疗诱导的细胞凋亡，但这种作用在前者中更为明显。在药物诱导的细胞凋亡过程中，MRITα1/cFLIP（L）的表达降低，而MRITα1/cFLIP（L）的外源性表达会延迟药物诱导的细胞凋亡过程中半胱天冬酶-8和-3的激活。这些结果表明，MRITα1/cFLIPL可能是死亡受体诱导和化疗诱导的细胞凋亡的重要决定因素，旨在下调其表达的策略值得进一步研究，作为克服癌症治疗多药耐药性的一种方法。
