Induction of PPARβ and prostacyclin (PGI2) synthesis by Raf signaling:: failure of PGI2 to activate PPARβ

A role for the nuclear receptor peroxisome proliferator-activated receptor-beta (PPAR beta) in oncogenesis has been suggested by a number of observations but its precise role remains elusive. Prostaglandin I-2 (PGI(2), prostacyclin), a major arachidonic acid (AA) derived cyclooxygenase (Cox) product, has been proposed as a PPAR beta agonist. Here, we show that the 4-hydroxytamoxifen (4-OHT) mediated activation of a C-Raf-estrogen receptor fusion protein leads to the induction of both the PPAR beta and Cox-2 genes, concomitant with a dramatic increase in PGI(2) synthesis. Surprisingly, however, 4-OHT failed to activate PPAR beta transcriptional activity, indicating that PGI(2) is insufficient for PPAR beta activation. In agreement with this conclusion, the overexpression of ectopic Cox-2 and PGI(2) synthase (PGIS) resulted in massive PGI(2) synthesis but did not activate the transcriptional activity of PPAR beta. Conversely, inhibition of PGIS blocked PGI(2) synthesis but did not affect the AA mediated activation of PPAR beta. Our data obtained with four different cell types and different experimental strategies do not support the prevailing opinion that PGI(2) plays a significant role in the regulation of PPAR beta.