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J. Biol. Chem., Vol. 281, Issue 16, 10954-10967, April 21, 2006

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Aryl Hydrocarbon Receptor Modulation of Tumor Necrosis Factor--induced Apoptosis and Lysosomal Disruption in a Hepatoma Model That Is Caspase-8-independent^*

Joseph A. Caruso, Patricia A. Mathieu, Aby Joiakim, Hong Zhang, and John J. Reiners, Jr.¹

From the Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan 48201 and Gene Trove Division, Isis Pharmaceuticals, Inc., Carlsbad, California 92008

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 tumor necrosis factor- (TNF) + 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 + 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-B activation. However, Bid and 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 + CHX disrupted late endosomes/lysosomes in only AhR-containing cells. Stabilization of acidic organelles with 3-O-methylsphingomyelin inhibited TNF + 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 the activation of pro-caspases-3/7 in cultures treated with TNF + CHX. Similar suppressive effects occurred in cultures transfected with murine Bid antisense oligonucleotides. These studies showed that in cells where pro-caspase-8 is not activated, TNF + 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.

Received for publication, August 1, 2005 , and in revised form, January 11, 2006.

^* This work was supported by NIEHS Grant ES009392 from the National Institutes of Health and was assisted by the Cell Culture, Imaging and Cytometry, and Protein and Proteomics Facility Cores. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table I and supplemental Figs. 1-5.

¹ To whom correspondence should be addressed: Institute of Environmental Health Sciences, Wayne State University, 2727 Second Ave., Detroit, MI 48201. Tel.: 313-963-7662; Fax: 313-577-0082; E-mail: john.reiners.jr{at}wayne.edu.

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