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Endothelin Receptor B Inhibition Triggers Apoptosis and Enhances Angiogenesis in Melanomas

Lahav, Ronit and Suvà, Mario-Luca and Rimoldi, Donata and Patterson, Paul H. and Stamenkovic, Ivan (2004) Endothelin Receptor B Inhibition Triggers Apoptosis and Enhances Angiogenesis in Melanomas. Cancer Research, 64 (24). pp. 8945-8953. ISSN 0008-5472. doi:10.1158/0008-5472.CAN-04-1510.

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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.

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Additional Information:© 2004 American Association for Cancer. Received 4/29/04; revised 9/16/04; accepted 10/7/04. Swiss National Research Foundation Grant 3100-65090.01 (I. Stamenkovic) and the Molecular Oncology National Center of Competence in Research. We thank Rene Bernards for the pSuper plasmid.
Funding AgencyGrant Number
Swiss National Research Foundation3100-65090.01
Molecular Oncology National Center of Competence in ResearchUNSPECIFIED
Issue or Number:24
Record Number:CaltechAUTHORS:20160212-090456507
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Official Citation:Endothelin Receptor B Inhibition Triggers Apoptosis and Enhances Angiogenesis in Melanomas Ronit Lahav, Mario-Luca Suvà, Donata Rimoldi, Paul H. Patterson, and Ivan Stamenkovic Cancer Res December 15, 2004 64:8945-8953; doi:10.1158/0008-5472.CAN-04-1510
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:64456
Deposited By: Ruth Sustaita
Deposited On:19 Feb 2016 20:51
Last Modified:10 Nov 2021 23:31

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