Author/Authors :
Ricci، نويسنده , , M. Stacey and Kim، نويسنده , , Seok-Hyun and Ogi، نويسنده , , Kazuhiro and Plastaras، نويسنده , , John P. and Ling، نويسنده , , Jianhua and Wang، نويسنده , , Wenge and Jin، نويسنده , , Zhaoyu and Liu، نويسنده , , Yingqiu Y. and Dicker، نويسنده , , David T. and Chiao، نويسنده , , Paul J. and Flaherty، نويسنده , , Keith T. and Smith، نويسنده , , Charles D. and El-Deiry، نويسنده , , Wafik S. El-Deiry and Yigong Shi، نويسنده ,
Abstract :
Summary
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.
