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The Peroxisome Proliferator-Activated Receptor (PPAR) Ligands 15-Deoxy-^12,14-Prostaglandin J₂ and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPAR-Independent Mechanisms¹

Denise M. Ray^*, Filiz Akbiyik^*, and Richard P. Phipps^2,*

^* Departments of Environmental Medicine, Microbiology, and Immunology, and Lung Biology and Disease Program, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642; and Department of Biochemistry, Hacettepe University, Ankara, Turkey

Peroxisome proliferator-activated receptor (PPAR) is a transcription factor important for adipogenesis and more recently has been shown to be an anticancer target. PPAR ligands, including the endogenous ligand 15-deoxy-^12,14-PGJ₂ (15d-PGJ₂) and synthetic ligands like ciglitazone and troglitazone, all induce apoptosis in normal and malignant human B lymphocytes, but the dependency of PPAR for apoptosis induction is unknown. In this study, we used a PPAR dominant-negative approach and a small molecule irreversible PPAR antagonist and found that these inhibitors prevented PPAR activation but did not prevent B cell apoptosis induced by 15d-PGJ₂ or ciglitazone. In addition, a PPAR agonist that is a structural analog of 15d-PGJ₂, and lacks the electrophilic carbon of the 15d-PGJ₂ cyclopentenone ring, activated PPAR but did not kill B lymphocytes, further supporting a non-PPAR-mediated mechanism. To further investigate the apoptotic mechanism, the effects of 15d-PGJ₂ and ciglitazone on reactive oxygen species were investigated. 15d-PGJ₂, but not ciglitazone, potently induced reactive oxygen species in B lymphocytes, implicating the reactive nature of the 15d-PGJ₂ structure in the apoptosis mechanism. In addition, 15d-PGJ₂ caused an almost complete depletion of intracellular glutathione. Moreover, incubation with glutathione reduced ethyl ester, an antioxidant, prevented apoptosis induced by 15d-PGJ₂, but not by ciglitazone. These findings indicate that the expression of PPAR may not be predictive of whether a normal or malignant B lineage cell is sensitive to PPAR agonists. Furthermore, these new findings support continued investigation into the use of PPAR agonists as agents to attenuate normal B cell responses and as anti-B cell lymphoma agents.

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.

¹ This work was supported by National Institutes of Health Grants DE011390 and ES01247. D.M.R. was supported by the Rochester Training Program in Oral Infectious Diseases, T32-DE07165. F.A. was supported by the International Union Against Cancer Fellowship Program and The Scientific and Technical Research Council of Turkey (TUBITAK)/NATO-A2.

² Address correspondence and reprint requests to Dr. Richard P. Phipps, Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Box 850, 601 Elmwood Avenue, Rochester, NY 14642. E-mail address: richard_phipps{at}urmc.rochester.edu

³ Abbreviations used in this paper: PPAR, peroxisome proliferator-activated receptor; 15d-PGJ₂, 15-deoxy-^12,14-PG J₂; GSH, glutathione; GSH-EE, glutathione-reduced ethyl ester; DN, dominant negative; PPRE, PPAR response element; ROS, reactive oxygen species; DiOC₆(3), 3,3'-dihexyloxacarbocyanide iodide; carboxy-H₂DCFDA, 5-(and-6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate, -gal, -galactosidase.