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Journal of Lipid Research, Vol. 43, 1818-1828, November 2002
Copyright © 2002 by Lipid Research, Inc.

15-Deoxy-^12,14-prostaglandin J₂-induced apoptosis does not require PPAR in breast cancer cells

Carl E. Clay^,, Arta Monjazeb^*, Jacqueline Thorburn^*, Floyd H. Chilton^,, and Kevin P. High^1,,**

^* Department of Cancer Biology, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston Salem, NC 27157
Department of Internal Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston Salem, NC 27157
Section of Pulmonary Critical Care, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston Salem, NC 27157
^** Section of Infectious Diseases, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston Salem, NC 27157
Department of Physiology and Pharmacology, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston Salem, NC 27157

¹ To whom correspondence should be addressed. e-mail: khigh{at}wfubmc.edu

Naturally occurring derivatives of arachidonic acid are potent agonists for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR) and block cancer cell proliferation through the induction of apoptosis. We have previously reported that induction of apoptosis using cyclopentenone prostaglandins of the J series, including 15deoxy^12,14PGJ₂ (15dPGJ₂), is associated with a high degree of PPAR-response element (PPRE) activity and requires early de novo gene expression in breast cancer cells. In the current study, we used pharmacologic and genetic approaches to test the hypothesis that PPAR is required for 15dPGJ₂-induced apoptosis. The PPAR agonists 15dPGJ₂, trogliltazone (TGZ), and GW7845, a synthetic and highly selective tyrosine-based PPAR agonist, all increased transcriptional activity of PPAR, and expression of CD36, a PPAR-dependent gene. Transcriptional activity and CD36 expression was reduced by GW9662, a selective and irreversible PPAR antagonist, but GW9662 did not block apoptosis induced by 15dPGJ₂. Moreover, dominant negative expression of PPAR blocked PPRE transcriptional activity, but did not block 15dPGJ₂-induced apoptosis.

These studies show that while 15dPGJ₂ activates PPRE-mediated transcription, PPAR is not required for 15dPGJ₂-induced apoptosis in breast cancer cells. Other likely mechanisms through which cyclopentenone prostaglandins induce apoptosis of cancer cells are discussed.

Abbreviations: CDDO, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; DN, dominant negative PPAR; 15dPGJ₂, 15deoxy^12,14PGJ₂; PPAR, peroxisome proliferator-activated receptor gamma; PPRE, PPAR-response element; ROS, reactive oxygen species; TGZ, troglitazone; TZD, thiazolidinedione; WT, wild type PPAR

Supplementary key words cyclopentenone prostaglandins • arachidonic acid metabolism • peroxisome proliferator-activated receptor

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