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

被引:36
作者
Sanchez, T [1 ]
Moreno, JJ [1 ]
机构
[1] Univ Barcelona, Fac Farm, Dept Fisiol, Sch Pharm, E-08028 Barcelona, Spain
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2002年 / 282卷 / 02期
关键词
arachidonic acid; cyclooxygenase; prostaglandin G/H synthase; phospholipase A(2);
D O I
10.1152/ajpcell.00128.2001
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Recent studies have suggested that prostaglandin E-2 (PGE(2)) subtype receptors (EP) are involved in cellular proliferation and tumor development. We studied the role of EP1 and EP4 PGE(2) 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 similar to100 and similar to30 muM, 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 G(0)/G(1) 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 G(0)/G(1) accumulation caused by AH-6809 seems to be intracellular Ca2+ concentration ([Ca2+](i)) dependent, because a 6-h 1 muM thapsigargin treatment allowed G(0)/G(1)-arrested cells to enter S phase. Similarly, treatment with 20 muM forskolin for 6 h allowed S-phase and G(2)/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 PGE(2) interaction with its different subtype receptors regulates progression through the cell cycle by modulating cAMP and [Ca2+](i).
引用
收藏
页码:C280 / C288
页数:9
相关论文
共 61 条
[1]  
ALEXANDROW MG, 1995, CANCER RES, V55, P1452
[2]   CALCIUM SIGNALING AND CELL-PROLIFERATION [J].
BERRIDGE, MJ .
BIOESSAYS, 1995, 17 (06) :491-500
[3]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[4]   Transfection of an active cytochrome P450 arachidonic acid epoxygenase indicates that 14,15-epoxyeicosatrienoic acid functions as an intracellular second messenger in response to epidermal growth factor [J].
Chen, JK ;
Wang, DW ;
Falck, JR ;
Capdevila, J ;
Harris, RC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (08) :4764-4769
[5]   A NOVEL INHIBITORY PROSTANOID RECEPTOR IN PIGLET SAPHENOUS-VEIN [J].
COLEMAN, RA ;
GRIX, SP ;
HEAD, SA ;
LOUTTIT, JB ;
MALLETT, A ;
SHELDRICK, RLG .
PROSTAGLANDINS, 1994, 47 (02) :151-168
[6]  
Coleman RA, 1985, BRIT J PHARMACOL, V85, P273
[7]   Endogenous EP4 prostaglandin receptors coupled positively to adenylyl cyclase in Chinese hamster ovary cells:: pharmacological characterization [J].
Crider, JY ;
Griffin, BW ;
Sharif, NA .
PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, 2000, 62 (01) :21-26
[8]  
DESDOUETS C, 1995, MOL CELL BIOL, V15, P3301
[9]   cAMP-dependent positive control of cyclin A2 expression during G1/S transition in primary hepatocytes [J].
Desdouets, C ;
Thoresen, GH ;
Senamaud-Beaufort, C ;
Christoffersen, T ;
Brechot, C ;
Sobczak-Thepot, J .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 261 (01) :118-122
[10]   Cyclooxygenase in biology and disease [J].
Dubois, RN ;
Abramson, SB ;
Crofford, L ;
Gupta, RA ;
Simon, LS ;
Van De Putte, LBA ;
Lipsky, PE .
FASEB JOURNAL, 1998, 12 (12) :1063-1073