Journal
CANCER CELL
Volume 12, Issue 1, Pages 66-80Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2007.05.006
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Funding
- NCI NIH HHS [CA97100, CA98101, CA75138, CA105008] Funding Source: Medline
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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-kappa B. Both Myc and the multikinase inhibitor sorafenib block NF-kappa B. 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.
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