Reduction of TRAIL-Induced Mcl-1 and cIAP2 by c-Myc or Sorafenib Sensitizes Resistant Human Cancer Cells to TRAIL-Induced Death

• Published in: Cancer cell Vol. 12; no. 1; pp. 66 - 80
• Main Authors: Ricci, M. Stacey, Kim, Seok-Hyun, Ogi, Kazuhiro, Plastaras, John P., Ling, Jianhua, Wang, Wenge, Jin, Zhaoyu, Liu, Yingqiu Y., Dicker, David T., Chiao, Paul J., Flaherty, Keith T., Smith, Charles D., El-Deiry, Wafik S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2007
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Baculoviral IAP Repeat-Containing 3 Protein; Benzenesulfonates - pharmacology; Cell Line, Tumor; CELLCYCLE; Female; Humans; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - physiology; Mice; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Niacinamide - analogs & derivatives; Phenylurea Compounds; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - physiology; Proto-Oncogene Proteins c-myc - physiology; Pyridines - pharmacology; TNF-Related Apoptosis-Inducing Ligand - physiology; Transcription, Genetic - physiology; Ubiquitin-Protein Ligases; CELLCYCLE
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2007.05.006

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.