A genome-wide expression profile and system-level integration of nuclear factor kappa B regulated genes reveals fundamental metabolic adaptations during cell growth and survival.
A murine lung alveolar carcinoma cell line (WT-Line 1) and its equally tumorigenic but non-malignant derivative transduced with a dominant negative inhibitor of NF-kappaB (mI-kappaB-Line 1), were profiled on the Affymetrix 19000 gene array platform. Two differentially expressed gene clusters were identified and integrated into a functional model. The downregulation of anti-oxidant defenses, in mI-kappaB-Line 1 cells, correlates with high levels of reactive oxygen species (ROS) and ROS damage to cellular macromolecules while the upregulation of metabolic nuclear receptors correlates with an adaptive/survival response, which involves a shift in energy metabolism toward beta-oxidative respiration. Accordingly, mI-kappaB-Line 1 cells are markedly sensitized to pharmacologic inhibition of beta-oxidative respiration. These findings are indicative of compensatory changes that could undermine anti-cancer therapies targeting NF-kappaB.
Andela
Valentine B
VB
The James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA. vandela@med.miami.edu
Schwarz
Edward M
EM
O'Keefe
Regis J
RJ
Puzas
Edward J
EJ
Rosenblatt
Joseph D
JD
Rosier
Randy N
RN
D000222:Adaptation, Physiological / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics* / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D051379:Mice; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000032:analysis
D016328:NF-kappa B; D011506:Proteins; D017382:Reactive Oxygen Species