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