期刊
ONCOGENE
卷 25, 期 6, 页码 838-848出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209122
关键词
c-FLIP; 5-fluorouracil; oxaliplatin; irinotecan; apoptosis
资金
- Medical Research Council [G0400302] Funding Source: Medline
- Medical Research Council [G0400302] Funding Source: researchfish
- MRC [G0400302] Funding Source: UKRI
FLIP inhibits caspase 8 activation and apoptosis mediated by death receptors such as Fas and DR5. We studied the effect of c-FLIP on the apoptotic response to chemotherapies used in colorectal cancer (CRC) (5-fluorouracil, oxaliplatin and irinotecan). Simultaneous downregulation of both c-FLIP splice forms c-FLIPL and c-FLIPS with siRNA synergistically enhanced chemotherapy-induced apoptosis in p53 wild-type (HCT116p53(+/+), RKO), null (HCT116p53(-/-)) and mutant (H630) CRC cell lines. Furthermore, overexpression of c-FLIPL, but not c-FLIPS, potently inhibited apoptosis induced by chemotherapy in HCT116p53(-/-) cells, suggesting that c-FLIPL was the more important splice form in mediating chemoresistance. In support of this, siRNA specifically targeted against c-FLIPL synergistically enhanced chemotherapy-induced apoptosis in a manner similar to the siRNA targeted against both splice forms. Inhibition of caspase 8 blocked the enhanced apoptosis induced by c-FLIP-targeted (FT) siRNA and chemotherapy. Furthermore, we found that downregulating cell surface DR5, but not Fas, also inhibited apoptosis induced by FT siRNA and chemotherapy. Interestingly, these effects were not dependent on activation of DR5 by its ligand TRAIL. These results indicate that c-FLIP inhibits TRAIL-independent, DR5- and caspase 8-dependent apoptosis in response to chemotherapy in CRC cells. Moreover, targeting c-FLIP in combination with existing chemotherapies may have therapeutic potential for the treatment of CRC.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据