15-Deoxy-delta12,14-prostaglandin J2-induced apoptosis does not require PPARgamma in breast cancer cells.
Naturally occurring derivatives of arachidonic acid are potent agonists for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) 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 15deoxydelta(12,14)PGJ(2) (15dPGJ(2)), 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 PPARgamma is required for 15dPGJ(2)-induced apoptosis. The PPARgamma agonists 15dPGJ(2), trogliltazone (TGZ), and GW7845, a synthetic and highly selective tyrosine-based PPARgamma agonist, all increased transcriptional activity of PPARgamma, and expression of CD36, a PPARgamma-dependent gene. Transcriptional activity and CD36 expression was reduced by GW9662, a selective and irreversible PPARgamma antagonist, but GW9662 did not block apoptosis induced by 15dPGJ(2). Moreover, dominant negative expression of PPARgamma blocked PPRE transcriptional activity, but did not block 15dPGJ(2)-induced apoptosis. These studies show that while 15dPGJ(2) activates PPRE-mediated transcription, PPARgamma is not required for 15dPGJ(2)-induced apoptosis in breast cancer cells. Other likely mechanisms through which cyclopentenone prostaglandins induce apoptosis of cancer cells are discussed.
Clay
Carl E
CE
Department of Cancer Biology, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston Salem, NC 27157, USA.
Monjazeb
Arta
A
Thorburn
Jacqueline
J
Chilton
Floyd H
FH
High
Kevin P
KP
D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015230:Prostaglandin D2