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ToxSci Advance Access published online on March 30, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm071
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

An L-tyrosine Derivative and PPAR{gamma} Agonist, GW7845, Activates a Multi-Faceted Caspase Cascade in Bone Marrow B Cells

Jennifer J. Schlezinger*, Jessica K. Emberley{dagger}, Stephanie L. Bissonnette* and David H. Sherr*

* Department of Environmental Health, Boston University School of Public Health {dagger} Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA

Correspondence to: Jennifer J. Schlezinger, Ph.D., Boston University School of Public Health, Dept. of Environmental Health, 715 Albany Street, R-405, Boston, MA 02118, Telephone: 617-638-6461, Fax: 617-638-6463, Email: jschlezi{at}bu.edu

Received January 17, 2007; revision received March 23, 2007; accepted March 23, 2007


  Abstract

Apoptosis is a critical event in the deletion of B lymphocytes prior to their migration to the periphery. Synthetic PPAR{gamma} agonists, including the drug GW7845 and the environmental contaminant mono-(2-ethylhexyl) phthalate, as well as an endogenous ligand, 15-deoxy-{Delta}12,14-prostaglandin J2, induce clonally unrestricted apoptosis in pro/pre-B cells. Considering that PPAR{gamma} agonists are used clinically for the treatment of diabetes and postulated to be useful as chemotherapeutics, we used GW7845 as a model PPAR{gamma} agonist to examine the mechanism of cell death that may contribute to tumor killing as well as normal bone marrow B lymphocyte toxicity. GW7845 induced rapid mitochondrial membrane depolarization and release of cytochrome c, along with nearly concurrent activation of capases-2, -3, -8 and -9 in primary pro-B cells and BU-11 cells, a non-transformed pro/pre-B cell line. GW7845-induced apoptosis was reduced significantly in Bax deficient and Apaf-1 mutant primary pro-B cells, supporting the conclusion that GW7845-induced apoptosis is mitochondria- and apoptosome-dependent. Using VAD-FMK as a pan-caspase inhibitor, we demonstrated that an initial cytochrome c release occurred independently of caspase activation and that only caspase-9 activation is partially caspase-independent. The attenuation of GW7845-induced apoptosis by multiple FMK-labeled peptide sequences suggests that multiple caspase pathways are responsible for initiating and executing apoptosis. The strong activation of Bid provides a mechanism by which caspase-2, -3, and -8 may amplify the apoptotic signal. These data support the hypothesis that pharmacologic concentrations of PPAR{gamma} agonists induce an intrinsic apoptotic pathway that is driven in normal bone marrow B cells by multiple amplification loops.

Key Words: PPAR{gamma}; chemotherapy; bone marrow toxicity; apoptosis.


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S. L. Bissonnette, J. E. Teague, D. H. Sherr, and J. J. Schlezinger
An Endogenous Prostaglandin Enhances Environmental Phthalate-Induced Apoptosis in Bone Marrow B Cells: Activation of Distinct but Overlapping Pathways
J. Immunol., August 1, 2008; 181(3): 1728 - 1736.
[Abstract] [Full Text] [PDF]


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