Cancer Cell
Volume 12, Issue 1, 10 July 2007, Pages 66-80
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Article
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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Summary

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.

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Present address: NCI/FDA Interagency Oncology Task Force, Division of Monoclonal Antibodies/CDER/FDA, 29 Lincoln Drive, NIH Building 29B, HFD-123, Bethesda, MD 20892, USA.

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Present address: Genentech, South San Francisco, CA 94080, USA.

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Present address: Medical University of South Carolina, Charleston, SC 29425, USA.

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These authors contributed equally to this work.