Endothelin receptor B inhibition triggers apoptosis and enhances angiogenesis in melanomas

Details

Serval ID
serval:BIB_A155EE79C31E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Endothelin receptor B inhibition triggers apoptosis and enhances angiogenesis in melanomas
Journal
Cancer Research
Author(s)
Lahav  R., Suva  M. L., Rimoldi  D., Patterson  P. H., Stamenkovic  I.
ISSN
0008-5472 (Print)
Publication state
Published
Issued date
2004
Volume
64
Number
24
Pages
8945-8953
Notes
PT - Journal Article PT - Research Support, Non-U.S. Gov't
Abstract
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
Keywords
Apoptosis/drug effects/physiology/Caspase 6/Caspases/metabolism/Cell Cycle Proteins/biosynthesis/Cell Line,Tumor/Disease Progression/Enzyme Activation/Humans/Lymphatic Metastasis/Melanoma/blood supply/drug therapy/Pathology/secondary/Neovascularization,Pathologic/Oligonucleotide Array Sequence Analysis/Oligopeptides/pharmacology/Piperidines/Poly(ADP-ribose) Polymerases/Receptor,Endothelin B/antagonists & inhibitors/Skin Neoplasms
Pubmed
Web of science
Open Access
Yes
Create date
29/01/2008 18:36
Last modification date
20/08/2019 15:07
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