An L-tyrosine derivative and PPARgamma agonist, GW7845, activates a multifaceted caspase cascade in bone marrow B cells.

Abstract

Apoptosis is a critical event in the deletion of B lymphocytes prior to their migration to the periphery. Synthetic peroxisome proliferator activated receptor gamma (PPARgamma) 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 J(2), induce clonally unrestricted apoptosis in pro/pre-B cells. Considering that PPARgamma agonists are used clinically for the treatment of diabetes and postulated to be useful as chemotherapeutics, we used GW7845 as a model PPARgamma 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 nontransformed 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 benzyloxycarbonyl-VAD-fluoromethyl ketone (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 was 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 caspases-2, -3, and -8 may amplify the apoptotic signal. These data support the hypothesis that pharmacologic concentrations of PPARgamma agonists induce an intrinsic apoptotic pathway that is driven in normal bone marrow B cells by multiple amplification loops.

• Authors: Jennifer J Schlezinger, Jessica K Emberley, Stephanie L Bissonnette, David H Sherr
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 98 Issue 1 Pg. 125-36 (Jul 2007) ISSN: 1096-6080 [Print] United States
• PMID: 17400580 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Caspase Inhibitors
• Oxazoles
• PPAR gamma
• GW 7845
• Tyrosine
• Cytochromes c
• Caspases

Topics

• Animals
• Apoptosis (drug effects)
• Bone Marrow Cells (drug effects, enzymology)
• Caspase Inhibitors
• Caspases (metabolism)
• Cytochromes c (metabolism)
• Immunoblotting
• Membrane Potentials (drug effects)
• Mice
• Mice, Inbred C57BL
• Mitochondrial Membranes (drug effects)
• Oxazoles (pharmacology)
• PPAR gamma (agonists)
• Signal Transduction (drug effects)
• Tyrosine (analogs & derivatives, pharmacology)