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 susceptibility to apoptosis was examined in the murine hepatoma 1c1c7 cell line and a series of variants having different levels of AHR expression. Exposure of 1c1c7 cultures to N-acetylsphingosine (C2-ceramide) caused a concentration-dependent inhibition of cell proliferation, loss of viability, and induction of apoptosis as monitored by analyses of DNA fragmentation and caspase activation. A variant cell line (Tao) having approximately 10% of the AHR content of 1c1c7 cells also arrested following exposure to C2-ceramide, but did not undergo apoptosis. Modulation of 1c1c7 and Tao AHR contents by transfection of Ahr antisense and sense constructs, respectively, confirmed the relationship between AHR content and susceptibility to C2-ceramide-induced apoptosis. C2-ceramide also induced the apoptosis of an AHR-containing cell line lacking the aryl hydrocarbon receptor nuclear translocator protein. AHR ligands (i.e. 2,3,7,8-tetrachlorodibenzo-p-dioxin and alpha-naphthoflavone) neither induced apoptosis nor modulated the development of apoptosis in C2-ceramide-treated 1c1c7 cultures. AHR content did not affect staurosporine- or doxorubicin-induced apoptosis. These results suggest the AHR modulates aspects of ceramide signaling associated with the induction of apoptosis but not cell cycle arrest, and does so by a mechanism that is independent of its interaction with aryl hydrocarbon receptor nuclear translocator and exogenous AHR ligands.
Reiners
J J
JJ
Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201, USA. john.reiners.jr@wayne.edu
Clift
R E
RE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology; D014407:Tumor Cells, Cultured
C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; C064769:N-acetylsphingosine; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004317:Doxorubicin; D019311:Staurosporine; D013110:Sphingosine