Aryl hydrocarbon receptor modulation of TNFalpha -induced apoptosis and lysosomal disruption in a hepatoma model that is caspase-8 independent Export

@article{citeulike:4114684, abstract = {Recent studies suggest that the aryl hydrocarbon receptor (AhR) modulates susceptibilities to some pro-apoptotic agents. AhR-containing murine hepatoma 1c1c7 cultures underwent apoptosis following exposure to TNF[alpha] + cycloheximide (CHX). In contrast, Tao cells, an AhR-deficient variant of the 1c1c7 line, were refractory to this treatment. AhR sense/antisense transfection studies demonstrated that AhR contents influenced susceptibility to the pro-apoptotic effects of TNF[alpha] + CHX. 1c1c7 cells and all variants expressed comparable amounts of TNF receptor-1 and TRADD. However, no cell line expressed FADD, and consequently pro-caspase-8 was not activated. AhR content did not influence JNK and NF-[kappa]B activation. However, Bid, pro-caspase-9, -3 and -12 processing occurred only in AhR-containing cells. Analyses of cathepsin B and D activities in digitonin-permeabilized cultures, and the monitoring of cathepsin B/D co-localization with Lamp-1, indicated that TNF[alpha] + CHX disrupted late endosomes/lysosomes in only AhR-containing cells. Stabilization of acidic organelles with 3-O-methylsphingomyelin inhibited TNF[alpha] + CHX induced apoptosis. The cathepsin D inhibitor pepstatin A suppressed in vitro cleavage of Bid by 1c1c7 lysosomal extracts. It also delayed the induction of apoptosis, and partially prevented Bid cleavage and pro-caspases-3/7 activation in cultures treated with TNF[alpha] + CHX. Similar suppressive effects occurred in cultures transfected with murine Bid antisense oligonucleotides. These studies show that in cells where pro-caspase-8 is not activated, TNF[alpha] + CHX can initiate apoptosis through lysosomal disruption. Released proteases such as cathepsin D trigger the apoptotic program by activating Bid. Furthermore, in the absence of exogenous ligand, the AhR modulates lysosomal disruption/permeability. 10.1074/jbc.M508383200}, author = {Caruso, Joseph A. and Mathieu, Patricia A. and Joiakim, Aby and Zhang, Hong and Reiners, John J.}, citeulike-article-id = {4114684}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M508383200}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/16446372}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=16446372}, day = {30}, doi = {10.1074/jbc.M508383200}, journal = {J. Biol. Chem.}, keywords = {ahr, apoptosis, tnf-a}, month = {January}, pages = {M508383200+}, posted-at = {2009-02-27 22:39:30}, priority = {3}, title = {Aryl hydrocarbon receptor modulation of TNFalpha -induced apoptosis and lysosomal disruption in a hepatoma model that is caspase-8 independent}, url = {http://dx.doi.org/10.1074/jbc.M508383200}, year = {2006} }

TY - JOUR ID - citeulike:4114684 L3 - citeulike-article-id:4114684 N2 - Recent studies suggest that the aryl hydrocarbon receptor (AhR) modulates susceptibilities to some pro-apoptotic agents. AhR-containing murine hepatoma 1c1c7 cultures underwent apoptosis following exposure to TNF[alpha] + cycloheximide (CHX). In contrast, Tao cells, an AhR-deficient variant of the 1c1c7 line, were refractory to this treatment. AhR sense/antisense transfection studies demonstrated that AhR contents influenced susceptibility to the pro-apoptotic effects of TNF[alpha] + CHX. 1c1c7 cells and all variants expressed comparable amounts of TNF receptor-1 and TRADD. However, no cell line expressed FADD, and consequently pro-caspase-8 was not activated. AhR content did not influence JNK and NF-[kappa]B activation. However, Bid, pro-caspase-9, -3 and -12 processing occurred only in AhR-containing cells. Analyses of cathepsin B and D activities in digitonin-permeabilized cultures, and the monitoring of cathepsin B/D co-localization with Lamp-1, indicated that TNF[alpha] + CHX disrupted late endosomes/lysosomes in only AhR-containing cells. Stabilization of acidic organelles with 3-O-methylsphingomyelin inhibited TNF[alpha] + CHX induced apoptosis. The cathepsin D inhibitor pepstatin A suppressed in vitro cleavage of Bid by 1c1c7 lysosomal extracts. It also delayed the induction of apoptosis, and partially prevented Bid cleavage and pro-caspases-3/7 activation in cultures treated with TNF[alpha] + CHX. Similar suppressive effects occurred in cultures transfected with murine Bid antisense oligonucleotides. These studies show that in cells where pro-caspase-8 is not activated, TNF[alpha] + CHX can initiate apoptosis through lysosomal disruption. Released proteases such as cathepsin D trigger the apoptotic program by activating Bid. Furthermore, in the absence of exogenous ligand, the AhR modulates lysosomal disruption/permeability. 10.1074/jbc.M508383200 JF - J. Biol. Chem. TI - Aryl hydrocarbon receptor modulation of TNFalpha -induced apoptosis and lysosomal disruption in a hepatoma model that is caspase-8 independent SP - M508383200 KW - ahr KW - apoptosis KW - tnf-a AU - Caruso, Joseph AU - Mathieu, Patricia AU - Joiakim, Aby AU - Zhang, Hong AU - Reiners, John PY - 2006/01/30/ UR - http://dx.doi.org/10.1074/jbc.M508383200 ER -