Received for publication July 31, 2006.
Revised October 2, 2006.
Accepted for publication October 2, 2006.

LACK OF THE AHR LEADS TO IMPAIRED ACTIVATION OF AKT/PKB AND ENHANCED SENSITIVITY TO APOPTOSIS INDUCED VIA THE INTRINSIC PATHWAY

Abstract

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 utilized 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. Towards 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 PI3K-Akt/PKB and to a lesser degree, EGFR activation. These findings indicate that exploring the use of AHR antagonist as agents that enhance the pro-apoptotic actions of cancer therapies may be a valid approach.

Key words: AHR, Akt, Apoptosis, EGFR, UV, antagonist

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