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Am J Physiol Cell Physiol 282: C280-C288, 2002. First published October 3, 2001; doi:10.1152/ajpcell.00128.2001
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Vol. 282, Issue 2, C280-C288, February 2002

Role of EP1 and EP4 PGE2 subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation

Teresa Sanchez and Juan Jose Moreno

Department of Physiology, School of Pharmacy, Barcelona University, E-08028 Barcelona, Spain

Recent studies have suggested that prostaglandin E2 (PGE2) subtype receptors (EP) are involved in cellular proliferation and tumor development. We studied the role of 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 ~100 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+ concentration ([Ca2+]i) dependent, because a 6-h 1 µM thapsigargin treatment allowed G0/G1-arrested cells to enter S phase. Similarly, treatment with 20 µM forskolin for 6 h allowed S-phase and G2/M progression of AH-23848B-treated cells. This 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.

arachidonic acid; cyclooxygenase; prostaglandin G/H synthase; phospholipase A2


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