RESUMEN
MDA-MB-231, MCF7, and SKOV3 cancer cells, but not HEK-293 cells, expressed mRNA for the leukocyte G protein-coupled 5-oxo-eicosatetraenoate (ETE) OXE receptor. 5-Oxo-ETE, 5-oxo-15-OH-ETE, and 5-HETE stimulated the cancer cell lines but not HEK-293 cells to mount pertussis toxin-sensitive proliferation responses. Their potencies in eliciting this response were similar to their known potencies in activating leukocytes and OXE receptor-transfected cells. However, high concentrations of 5-oxo-ETE and 5-oxo-15-OH-ETE, but not 5-HETE, arrested growth and caused apoptosis in all four cell lines; these responses were pertussis toxin-resistant. The same high concentrations of the oxo-ETEs but again not 5-HETE also activated peroxisome proliferator-activated receptor (PPAR)-gamma. Pharmacological studies indicated that this activation did not mediate their effects on proliferation. These results are the first to implicate the OXE receptor in malignant cell growth and to show that 5-oxo-ETEs activate cell death programs as well as PPARgamma independently of this receptor.
Asunto(s)
Ácidos Araquidónicos/farmacología , Proliferación Celular/efectos de los fármacos , Receptores Eicosanoides/fisiología , Anilidas/farmacología , Apoptosis/efectos de los fármacos , Ácidos Araquidónicos/metabolismo , Sitios de Unión/genética , Caspasa 3 , Caspasas/metabolismo , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Expresión Génica/genética , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Ácidos Hidroxieicosatetraenoicos/farmacología , Mitosis/efectos de los fármacos , PPAR gamma/antagonistas & inhibidores , PPAR gamma/genética , PPAR gamma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/genética , Toxina del Pertussis/farmacología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Prostaglandina D2/análogos & derivados , Prostaglandina D2/metabolismo , Prostaglandina D2/farmacología , Unión Proteica , Receptores Eicosanoides/genética , TransfecciónRESUMEN
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.
