期刊
CANCER BIOLOGY & THERAPY
卷 7, 期 10, 页码 1648-1662出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.7.10.6623
关键词
vorinostat; sorafenib; CD95; c-FLIP-s; PDGFR beta; FLT3; autophagy; ceramide; cell death; ASMase
类别
资金
- Leukemia Society of America [6405-97]
- MUSC Lipidomics core [C06-RR018823]
- The Jimmy V. Foundation
- [R01-DK52825]
- [P01-CA104177]
- [R01-CA108520]
- [R01-CA63753]
- [R01-CA77141]
- NATIONAL CANCER INSTITUTE [R01CA063753, R01CA108520, R01CA061774, P01CA104177] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [C06RR018823] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK052825] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R37GM043880] Funding Source: NIH RePORTER
We recently noted that low doses of sorafenib and vorinostat interact in a synergistic fashion to kill carcinoma cells by activating CD95, and this drug combination is entering phase I trials. The present studies mechanistically extended our initial observations. Low doses of sorafenib and vorinostat, but not the individual agents, caused an acidic sphingomyelinase and fumonisin B1- dependent increase in CD95 surface levels and CD95 association with caspase 8. Knock down of CD95 or FADD expression reduced sorafenib/ vorinostat lethality. Signaling by CD95 caused PERK activation that was responsible for both promoting caspase 8 association with CD95 and for increased eIF2 alpha phosphorylation; suppression of eIF2a function abolished drug combination lethality. Cell killing was paralleled by PERK-and eIF2 alpha-dependent lowering of c-FLIP-s protein levels and overexpression of c-FLIP-s maintained cell viability. In a CD95-, FADD- and PERK-dependent fashion, sorafenib and vorinostat increased expression of ATG5 that was responsible for enhanced autophagy. Expression of PDGFR beta and FLT3 were essential for high dose single agent sorafenib treatment to promote autophagy. Suppression of PERK function reduced sorafenib and vorinostat lethality whereas suppression of ATG5 levels elevated sorafenib and vorinostat lethality. Overexpression of c-FLIP-s blocked apoptosis and enhanced drug-induced autophagy. Thus sorafenib and vorinostat promote ceramide-dependent CD95 activation followed by induction of multiple downstream survival regulatory signals: ceramide-CD95-PERK-FADD-pro-caspase 8 (death); ceramide-CD95-PERK-eIF2 alpha-down arrow c-FLIP-s ( death); ceramide-CD95- PERK-ATG5-autophagy (survival).
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