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Am J Physiol Cell Physiol (October 3, 2001). doi:10.1152/ajpcell.00128.2001
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Articles in PresS, published online ahead of print October 3, 2001
Am J Physiol Cell Physiol, 10.1152/ajpcell.00128.2001
Submitted on March 9, 2001
Accepted on September 28, 2001

Role of EP1 and EP4 prostaglandin E2 subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation.R2

Teresa Sanchez1 and Juan J Moreno1*

1 Physiology, Barcelona University, Barcelona, Spain

* To whom correspondence should be addressed. E-mail: moreno{at}farmacia.far.ub.es.

Recent studies have suggested that prostaglandin E2 (PGE2) subtype receptors (EP) are involved in cellular proliferation and tumor development. We studied the role of the EP1 and EP4 PGE2 subtype receptor antagonists, AH 6809 and AH 23848B, respectively, in serum-induced 3T6 fibroblast proliferation. This was significantly reduced in a dose-dependent manner (IC50~100µM and ~30 µM, respectively) to an almost complete inhibition, without any cytotoxic effect. However, the effect of each antagonist on 3T6 cell cycle progression clearly differed. Whereas the EP1 antagonist increased the G0/G1 population, the EP4 antagonist brought about an accumulation of cells in early S phase. These effects were associated with a decrease in cyclin D and E levels, in AH 6809-treated 3T6 cells, and lower cyclin A levels in AH 23848B-treated fibroblasts with respect to control cells. The G0/G1 accumulation caused by AH 6809 seems to be intracellular Ca2+oncentration ([Ca2+]i)-dependent, since a 6 hour-1 µM thapsigargin treatment allowed G0/G1-arrested cells to enter the S phase. In the same way, treatment with 20 µM forskolin for 6 hours allowed S-phase and G2/M progression of AH 23848B-treated cells. The present study shows that the inhibitory effect of the EP1 and EP4 antagonists on serum-induced 3T6 fibroblast growth is due to their effect at various levels of the cell cycle machinery, suggesting that PGE2-interaction with its different subtype receptors regulates progression through the cell cycle by modulating cAMP and [Ca2+]i.




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