Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death

Cancer Cell. 2007 Jul;12(1):66-80. doi: 10.1016/j.ccr.2007.05.006.

Abstract

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-kappaB. Both Myc and the multikinase inhibitor sorafenib block NF-kappaB. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Benzenesulfonates / pharmacology*
  • Cell Line, Tumor
  • 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*
  • Sorafenib
  • TNF-Related Apoptosis-Inducing Ligand / physiology*
  • Transcription, Genetic / physiology
  • Ubiquitin-Protein Ligases

Substances

  • Antineoplastic Agents
  • Benzenesulfonates
  • Inhibitor of Apoptosis Proteins
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Phenylurea Compounds
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Pyridines
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Niacinamide
  • Sorafenib
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases