This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lahav, R. Articles by Stamenkovic, I. Search for Related Content PubMed PubMed Citation Articles by Lahav, R. Articles by Stamenkovic, I.

Endothelin Receptor B Inhibition Triggers Apoptosis and Enhances Angiogenesis in Melanomas

¹ Division of Experimental Pathology, Institut Universitaire de Pathologie Université de Lausanne, Lausanne, Switzerland; ² Ludwig Institute, Lausanne Branch, Epalinges, Switzerland; and ³ Division of Biology, California Institute of Technology, Pasadena, California

Endothelin receptor B (ETRB or EDNRB) is overexpressed in most human melanomas and is proposed to provide a marker of melanoma progression. We have shown previously that inhibition of ETRB leads to increased human melanoma cell death in vitro and in vivo, resulting in shrinkage of tumors grown in immunocompromised mice. In the present work, we analyzed the effects of ETRB inhibition on 10 human melanoma cell lines derived from tumors at distinct stages of progression. Our observations suggest that the ETRB antagonist BQ788 induces apoptosis most effectively in metastatic melanoma cells. Microarray analysis shows that BQ788 treatment leads to a reduction in the expression of the survival factor BCL-2A1 and the DNA repair factor poly(ADP-ribose) polymerase 3 that is more pronounced in cells derived from metastatic than primary melanoma. Decreased cell viability was observed to correlate with reduction in ETRB expression, and reduction in ETRB protein levels by small interfering RNA led to an increase in cell death. Interestingly, reduction of ETRB expression by BQ788 was accompanied by a strong induction of VEGF expression and repression of the angiogenic suppressor gravin. These changes in gene expression correlated with increased angiogenesis in tumors injected with ETRB antagonist in vivo. Taken together, our observations suggest that ETRB may provide a potential therapeutic target in high-grade melanomas and identify candidate pathways that may be implicated in the regulation of cell survival and tumor progression associated with ETRB signaling.

This article has been cited by other articles:

				M.-N. Raymond, P. Robin, F. De Zen, G. Vilain, and Z. Tanfin Differential Endothelin Receptor Expression and Function in Rat Myometrial Cells and Leiomyoma ELT3 Cells Endocrinology, October 1, 2009; 150(10): 4766 - 4776. [Abstract] [Full Text] [PDF]

				C. Binder, T. Hagemann, S. Sperling, M. Schulz, T. Pukrop, M. J. Grimshaw, and H. Ehrenreich Stromal endothelin B receptor-deficiency inhibits breast cancer growth and metastasis Mol. Cancer Ther., August 1, 2009; 8(8): 2452 - 2460. [Abstract] [Full Text] [PDF]

				K. T. B. Mouchaers, I. Schalij, A. M. G. Versteilen, A. M. Hadi, G. P. van Nieuw Amerongen, V. W. M. van Hinsbergh, P. E. Postmus, W. J. van der Laarse, and A. Vonk-Noordegraaf Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H200 - H207. [Abstract] [Full Text] [PDF]

				M J Grimshaw Endothelins and hypoxia-inducible factor in cancer Endocr. Relat. Cancer, June 1, 2007; 14(2): 233 - 244. [Abstract] [Full Text] [PDF]

				F. Spinella, L. Rosano, V. Di Castro, S. Decandia, M. R. Nicotra, P. G. Natali, and A. Bagnato Endothelin-1 and Endothelin-3 Promote Invasive Behavior via Hypoxia-Inducible Factor-1{alpha} in Human Melanoma Cells Cancer Res., February 15, 2007; 67(4): 1725 - 1734. [Abstract] [Full Text] [PDF]

				R. K. Thirumaran, A. Thoelke, S. Ugurel, K. Hemminki, D. Schadendorf, and R. Kumar Re: association between endothelin receptor B nonsynonymous variants and melanoma risk. J Natl Cancer Inst, September 6, 2006; 98(17): 1252 - 1253. [Full Text] [PDF]

				Y. Berger, C. C. Bernasconi, and L. Juillerat-Jeanneret Targeting the endothelin axis in human melanoma: combination of endothelin receptor antagonism and alkylating agents. Experimental Biology and Medicine, June 1, 2006; 231(6): 1111 - 1119. [Abstract] [Full Text] [PDF]