Reduction of TRAIL-Induced Mcl-1 and cIAP2 by c-Myc or Sorafenib Sensitizes Resistant Human Cancer Cells to TRAIL-Induced Death
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- 作者：M. Stacey Ricci ; Seok-Hyun Kim ; Kazuhiro Ogi ; John P. Plastaras ; Jianhua Ling ; Wenge Wang ; Zhaoyu Jin ; Yingqiu Y. Liu ; David T. Dicker ; Paul J. Chiao ; Keith T. Flaherty ; Charles D. Smith ; Wafik S. El
- 关键词：CELLCYCLE
- 刊名：Cancer Cell
- 出版年：2007
- 出版时间：10 July 2007
- 年：2007
- 卷：12
- 期：1
- 页码：66-80
- 全文大小：1809 K
文摘
Cells expressing oncogenic c-Myc are sensitized to TNF superfamily proteins. c-Myc also is an important factor in determining whether a cell is sensitive to TRAIL-induced apoptosis, and it is well established that the mitochondrial pathway is essential for apoptosis induced by c-Myc. We investigated whether c-Myc action on the mitochondria is required for TRAIL sensitivity and found that Myc sensitized cells with defective intrinsic signaling to TRAIL. TRAIL induced expression of antiapoptotic Mcl-1 and cIAP2 through activation of NF-κB. Both Myc and the multikinase inhibitor sorafenib block NF-κB. Combining sorafenib with TRAIL in vivo showed dramatic efficacy in TRAIL-resistant tumor xenografts. We propose the combination of TRAIL with sorafenib holds promise for further development.