The Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) Ligands 15-Deoxy-{Delta}12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPAR{gamma}-Independent Mechanisms.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor important for adipogenesis and more recently has been shown to be an anticancer target. PPARgamma ligands, including the endogenous ligand 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) and synthetic ligands like ciglitazone and troglitazone, all induce apoptosis in normal and malignant human B lymphocytes, but the dependency of PPARgamma for apoptosis induction is unknown. In this study, we used a PPARgamma dominant-negative approach and a small molecule irreversible PPARgamma antagonist and found that these inhibitors prevented PPARgamma activation but did not prevent B cell apoptosis induced by 15d-PGJ(2) or ciglitazone. In addition, a PPARgamma agonist that is a structural analog of 15d-PGJ(2), and lacks the electrophilic carbon of the 15d-PGJ(2) cyclopentenone ring, activated PPARgamma but did not kill B lymphocytes, further supporting a non-PPARgamma-mediated mechanism. To further investigate the apoptotic mechanism, the effects of 15d-PGJ(2) and ciglitazone on reactive oxygen species were investigated. 15d-PGJ(2), but not ciglitazone, potently induced reactive oxygen species in B lymphocytes, implicating the reactive nature of the 15d-PGJ(2) structure in the apoptosis mechanism. In addition, 15d-PGJ(2) caused an almost complete depletion of intracellular glutathione. Moreover, incubation with glutathione reduced ethyl ester, an antioxidant, prevented apoptosis induced by 15d-PGJ(2), but not by ciglitazone. These findings indicate that the expression of PPARgamma may not be predictive of whether a normal or malignant B lineage cell is sensitive to PPARgamma agonists. Furthermore, these new findings support continued investigation into the use of PPARgamma agonists as agents to attenuate normal B cell responses and as anti-B cell lymphoma agents.[1]References
- The Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) Ligands 15-Deoxy-{Delta}12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPAR{gamma}-Independent Mechanisms. Ray, D.M., Akbiyik, F., Phipps, R.P. J. Immunol. (2006) [Pubmed]
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