Lack of the aryl hydrocarbon receptor leads to impaired activation of AKT/protein kinase B and enhanced sensitivity to apoptosis induced via the intrinsic pathway.
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that is best known for its role in mediating the toxicity of many environmental contaminants such as 2,3,7,8 tetrachlorodibenzo-p-dioxin. However, the endogenous role of AHR, especially with respect to the apoptotic process, is largely unknown and contradictory. In this report, we have used a mouse hepatoma cell line (Hepa1c1c7) and its AHR-deficient derivative (LA1) to examine the effect of differing AHR levels on apoptosis susceptibility, in particular, apoptosis regulated by the intrinsic pathway. Toward this end, the cells were subjected to UV irradiation, hydrogen peroxide, and serum starvation. Analyses of a number of different endpoints of apoptosis revealed that the LA1 cells were more sensitive to these stresses than the wild-type cells, indicating that the AHR plays a cytoprotective role in the face of stimuli that initiate the intrinsic apoptotic pathway. A direct role of the AHR in mediating this effect was confirmed using both pharmacological and molecular approaches. Further analyses imply that lack of the AHR leads to an impaired survival response mediated by phosphatidylinositol 3'-OH kinase-Akt/protein kinase B and, to a lesser degree, epidermal growth factor receptor activation. These findings indicate that exploring the use of the AHR antagonist as agents that enhance the proapoptotic actions of cancer therapies may be a valid approach.
Wu
Ran
R
Department of Molecular and Biomedical Pharmacology, MS305, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536, USA.
Zhang
Li
L
Hoagland
Martin S
MS
Swanson
Hollie I
HI
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
C091768:3'-methoxy-4'-nitroflavone; D005419:Flavonoids; D018336:Receptors, Aryl Hydrocarbon; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt