Aryl hydrocarbon receptor regulation of ceramide-induced apoptosis in murine hepatoma 1c1c7 cells - A function independent of aryl hydrocarbon receptor nuclear translocator

The relationship between aryl hydrocarbon receptor (AHR) content and suscep tibility to apoptosis was examined in the murine hepatoma 1c1c7 cell line a nd a series of variants having different levels of AHR expression. Exposure of 1c1c7 cultures to N-acetylsphingosine (C-2-ceramide) caused a concentra dion-dependent inhibition of cell proliferation, loss of viability, and ind uction of apoptosis as monitored by analyses of DNA fragmentation and caspa se activation. A variant cell line (Tao) having similar to 10% of the AHR c ontent of 1c1c7 cells also arrested following exposure to C-2-ceramide, but did not undergo apoptosis, Modulation of 1c1c7 and Tao AHR contents by tra nsfection of Ahr antisense and sense constructs, respectively, confirmed th e relationship between AHR content and susceptibility to C-2-ceramide-indue ed apoptosis. C-2-ceramide also induced the apoptosis of an AHR-containing cell line lacking the aryl hydrocarbon receptor nuclear translocator protei n. ABR ligands (Le. 2,3,7,8-tetrachlorodibenzo-p-dioxin and alpha-naphthofl avone) neither induced apoptosis nor modulated the development of apoptosis in C-2-ceramide-treated 1c1c7 cultures, AHR content did not affect stauros porine- or doxorubicin-induced apoptosis. These results suggest the ABR mod ulates aspects of ceramide signaling associated with the induction of apopt osis but not cell cycle arrest, and does so by a mechanism that is independ ent of its interaction with aryl hydrocarbon receptor nuclear translocator and exogenous AHR ligands.