Endothelin-1 promotes cell survival in renal cell carcinoma through the ETA receptor

被引:52
作者
Pflug, Beth R.
Zheng, Hong
Udan, Michael S.
D'Antonio, Jason M.
Marshall, Fray F.
Brooks, James D.
Nelson, Joel B.
机构
[1] Univ Pittsburgh, Dept Urol, Pittsburgh, PA 15232 USA
[2] Johns Hopkins Sch Med, Dept Urol, James Buchanan Brady Urol Inst, Baltimore, MD 21227 USA
[3] Emory Univ, Dept Urol, Atlanta, GA 30322 USA
[4] Stanford Univ, Sch Med, Dept Urol, Stanford, CA 94305 USA
关键词
renal cell carcinoma; endothelin-1; cell survival; endothelin receptors;
D O I
10.1016/j.canlet.2006.02.007
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Endothelin-1 (ET-1) is a potent vasoconstrictor that has been shown to significantly impact many benign and malignant tissues by signaling through its two cognate receptors: ETA and ETB. As ET-I has a role in both normal and diseased kidney, we initiated studies to investigate endothelin axis expression and function in renal cell carcinoma (RCC). In this study, relatively high levels of ET-1 were detected in all six human RCC cell lines investigated. RT-PCR and Southern analyses revealed that all six RCC cell lines expressed ETA receptor mRNA, while 3/6 cell lines also expressed ETB mRNA. High affinity ET-I binding occurred in all but one RCC cell line and quantitative RT-PCR demonstrated ETA mRNA expression in all six cell lines. Methylation of the ETB promoter (EDNRB) in 4/6 RCC cell lines was observed, suggesting a mechanism for repressed ETB expression. Moreover, methylation occurred in 32/48 of renal tumors and in 27/55 of histologically normal adjacent tissue samples studied, while no methylation was evident in any normal tissue isolated from nephrectomy or at autopsy. Functionally, ET-1 significantly inhibited paclitaxel-induced apoptosis in RCC cells through binding ETA with the ET-1 signaling mediated via the PI3-kinase/Akt pathway. Collectively, these data support the therapeutic targeting of the ETA receptor as a novel treatment strategy for RCC. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:139 / 148
页数:10
相关论文
共 59 条
[21]   ENDOTHELIN RECEPTOR SUBTYPE-B MEDIATES SYNTHESIS OF NITRIC-OXIDE BY CULTURED BOVINE ENDOTHELIAL-CELLS [J].
HIRATA, Y ;
EMORI, T ;
EGUCHI, S ;
KANNO, K ;
IMAI, T ;
OHTA, K ;
MARUMO, F .
JOURNAL OF CLINICAL INVESTIGATION, 1993, 91 (04) :1367-1373
[22]   Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension [J].
Hocher, B ;
ThoneReineke, C ;
Rohmeiss, P ;
Schmager, F ;
Slowinski, T ;
Burst, V ;
Siegmund, F ;
Quertermous, T ;
Bauer, C ;
Neumayer, HH ;
Schleuning, WD ;
Theuring, F .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 99 (06) :1380-1389
[23]   INSULIN STIMULATES PRODUCTION AND SECRETION OF ENDOTHELIN FROM BOVINE ENDOTHELIAL-CELLS [J].
HU, RM ;
LEVIN, ER ;
PEDRAM, A ;
FRANK, HJL .
DIABETES, 1993, 42 (02) :351-358
[24]   The effect of endothelin antagonists on renal ischaemia-reperfusion injury and the development of acute renal failure in the rat [J].
Huang, CL ;
Huang, CH ;
Hestin, D ;
Dent, PC ;
Barclay, P ;
Collis, M ;
Johns, EJ .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2002, 17 (09) :1578-1585
[25]   ESTABLISHMENT OF A NEW PROSTATIC-CARCINOMA CELL-LINE (TSU-PR1) [J].
IIZUMI, T ;
YAZAKI, T ;
KANOH, S ;
KONDO, I ;
KOISO, K .
JOURNAL OF UROLOGY, 1987, 137 (06) :1304-1306
[26]  
Ikeda Miwako, 1995, Clinical and Experimental Pharmacology and Physiology, V22, pS197, DOI 10.1111/j.1440-1681.1995.tb02879.x
[27]   THE HUMAN ENDOTHELIN FAMILY - 3 STRUCTURALLY AND PHARMACOLOGICALLY DISTINCT ISOPEPTIDES PREDICTED BY 3 SEPARATE GENES [J].
INOUE, A ;
YANAGISAWA, M ;
KIMURA, S ;
KASUYA, Y ;
MIYAUCHI, T ;
GOTO, K ;
MASAKI, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (08) :2863-2867
[28]  
INOUE A, 1989, J BIOL CHEM, V264, P14954
[29]  
Ivic MA, 1998, PATHOL BIOL, V46, P723
[30]   ENDOTHELIN RECEPTOR SUBTYPE-B MEDIATES AUTOINDUCTION OF ENDOTHELIN-1 IN RAT MESANGIAL CELLS [J].
IWASAKI, S ;
HOMMA, T ;
MATSUDA, Y ;
KON, V .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (12) :6997-7003