Suppression of prostaglandin E2 receptor subtype EP2 by PPARγ ligands inhibits human lung carcinoma cell growth

被引:64
作者
Han, SW [1 ]
Roman, J
机构
[1] Emory Univ, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Atlanta, GA 30322 USA
[2] Atlanta Vet Affairs Med Ctr, Atlanta, GA 30033 USA
关键词
D O I
10.1016/j.bbrc.2004.01.007
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Prostaglandin E-2 (PGE(2)), a major cyclooxygenase (COX-2) metabolite, plays important roles in tumor biology and its functions are mediated through one or more of its receptors EP1, EP2, EP3, and EP4. We have shown that the matrix glycoprotein fibronectin stimulates lung carcinoma cell proliferation via induction of COX-2 expression with subsequent PGE(2) protein biosynthesis. Ligands of peroxisome proliferator-activated receptor gamma (PPARgamma) inhibited this effect and induced cellular apoptosis. Here, we explore the role of the PGE(2) receptor EP2 in this process and whether the inhibition observed with PPARgamma ligands is related to effects on this receptor. We found that human non-small cell lung carcinoma cell lines (H1838 and H2106) express EP2 receptors, and that the inhibition of cell growth by PPARgamma ligands (GW1929, PGJ2, ciglitazone, troglitazone, and rosiglitazone [also known as BRL49653]) was associated with a significant decrease in EP2 mRNA and protein levels. The inhibitory effects of BRL49653 and ciglitazone, but not PGJ2, were reversed by a specific PPARgamma antagonist GW9662, suggesting the involvement of PPARgamma-dependent and -independent mechanisms. PPARgamma ligand treatment was associated with phosphorylation of extracellular regulated kinase (Erk), and inhibition of EP2 receptor expression by PPARy ligands was prevented by PD98095, an inhibitor of the MEK-1/Erk pathway. Butaprost, an EP2 agonist, like exogenous PGE(2) (dmPGE(2)), increased lung carcinoma cell growth, however, GW1929 and troglitazone blocked their effects. Our studies reveal a novel role for EP2 in mediating the proliferative effects of PGE(2) on lung carcinoma cells. PPARgamma ligands inhibit human lung carcinoma cell growth by decreasing the expression of EP2 receptors through Erk signaling and PPARgamma-dependent and -independent pathways. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:1093 / 1099
页数:7
相关论文
共 43 条
[1]   Prostaglandin E receptors and the kidney [J].
Breyer, MD ;
Breyer, RM .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2000, 279 (01) :F12-F23
[2]   AH6809 antagonizes non-small cell lung cancer prostaglandin receptors [J].
Casibang, M ;
Moody, TW .
LUNG CANCER, 2002, 36 (01) :33-42
[3]   Inhibition of IFN-γ-mediated inducible nitric oxide synthase induction by the peroxisome proliferator-activated receptor γ agonist, 15-deoxy-Δ12,14-prostaglandin J2, involves inhibition of the upstream Janus kinase/STAT1 signaling pathway [J].
Chen, CW ;
Chang, YH ;
Tsi, CJ ;
Lin, WW .
JOURNAL OF IMMUNOLOGY, 2003, 171 (02) :979-988
[4]  
Chen YX, 2003, WORLD J GASTROENTERO, V9, P2149
[5]   Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion [J].
Dohadwala, M ;
Batra, RK ;
Luo, J ;
Lin, Y ;
Krysan, K ;
Pold, M ;
Sharma, S ;
Dubinett, SM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (52) :50828-50833
[6]   Mechanisms of prostaglandin E2-induced interleukin-6 release in astrocytes:: possible involvement of EP4-like receptors, p38 mitogen-activated protein kinase and protein kinase C [J].
Fiebich, BL ;
Schleicher, S ;
Spleiss, O ;
Czygan, M ;
Hüll, M .
JOURNAL OF NEUROCHEMISTRY, 2001, 79 (05) :950-958
[7]   Prostaglandin E2-induced up-regulation of c-fos messenger ribonucleic acid is primarily mediated by 3′,5′-cyclic adenosine monophosphate in MC3T3-E1 osteoblasts [J].
Fitzgerald, J ;
Dietz, TJ ;
Hughes-Fulford, M .
ENDOCRINOLOGY, 2000, 141 (01) :291-298
[8]  
Han SW, 2003, CLIN CANCER RES, V9, P4627
[9]   RU486-induced growth inhibition of human endometrial cells involves the nuclear factor-κB signaling pathway [J].
Han, SW ;
Sidell, N .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2003, 88 (02) :713-719
[10]   Up-regulation of cyclooxygenase-2 gene expression by chorionic gonadotropin during the differentiation of human endometrial stromal cells into decidua [J].
Han, SW ;
Lei, ZM ;
Rao, CV .
ENDOCRINOLOGY, 1996, 137 (05) :1791-1797