Human Melanoma Cells Express Functional Endothelin-1 Receptors

Yohn, Joseph; Smith, Corinne J.; Stevens, Tanya R.; Hoffman, T. A.; Morelli, Joseph G.; Hurt, D. L.; Yanagisawa, Masashi; Kane, M. A.; Zamora, Martin R.

doi:10.1006/bbrc.1994.1722

Cited by 54 publications

(35 citation statements)

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“…Subsequent studies on primary cultured melanocyte precursor cells revealed multiple roles of ET B in growth/differentiation of the cells that apparently differ between the differentiation stages of the cells (12). In keeping with these findings, various human melanoma cell lines have been shown to express this receptor subtype (13,14), which indicates the possibility that each melanoma is derived from the fully differentiated cell, melanocyte, and retains the characteristics of undifferentiated melanocyte-precursor cells.…”

supporting

confidence: 54%

Endothelin-induced Apoptosis of A375 Human Melanoma Cells

Okazawa¹,

Shiraki²,

Ninomiya

et al. 1998

Journal of Biological Chemistry

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Endothelin-1 (ET-1) inhibited serum-dependent growth of asynchronized A375 human melanoma cells, and the growth inhibitory effect was markedly enhanced when ET-1 was applied to the cells synchronized at G 1 /S boundary by double thymidine blocks. Flow cytometric analysis revealed that ET-1 did not inhibit the cell cycle progression after the release of the block but caused a significant increase of the hypodiploid cell population that is characteristic of apoptotic cell death. ET-1-induced apoptosis was confirmed by the appearance of chromatin condensation on nuclear staining and DNA fragmentation on gel electrophoresis. The increase in the hypodiploid cell peak was manifest within 16 h of exposure to 5 nM ET-1. Within the same time range, ET-1 caused actin reorganization and drastic morphological changes of the surviving cells from epithelioid to an elongated bipolar shape. These phenotypical changes were preceded by ET-1-induced increase and nuclear accumulation of the tumor suppressor protein p53. All of these effects of ET-1 were mediated by ET B via a pertussis toxin-sensitive G protein. Flow cytometric analysis with fluorescent dye-labeled ET-1 revealed up-regulation of ET B expressed by the cells in G 1 /early S phases, and overexpression of the receptor protein by cDNA microinjection conferred the responsiveness (both apoptosis and morphological changes) to ET-1 irrespective of the position of the cell in the cell cycle. These results indicated the presence of ET B -mediated signaling pathways to apoptotic cell machinery and cytoskeletal organization. Furthermore, the densities of ET B expressed by individual A375 melanoma cells appeared to be regulated by a cell cycle-dependent mechanism, and the receptor density can be a limiting factor to control the apoptotic and cytoskeletal responses of the cells to ET-1. Although the molecular mechanisms remain to be elucidated, these findings added a new dimension to the diverse biological activities of ETs and also indicated a novel mechanism to control the responsiveness of the cell to the peptides.

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supporting

confidence: 54%

Endothelin-induced Apoptosis of A375 Human Melanoma Cells

Okazawa¹,

Shiraki²,

Ninomiya

et al. 1998

Journal of Biological Chemistry

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“…7,8 ETA are upregulated in prostate, 9 ovary 10 and breast cancers while ETB is overexpressed in melanoma. [11][12][13] Melanoma is an aggressive cancer that presents an increased incidence rate.…”

Section: Introductionmentioning

confidence: 99%

Rendomab B4, a monoclonal antibody that discriminates the human endothelin B receptor of melanoma cells and inhibits their migration

Borrull

Allard

Wijkhuisen

et al. 2016

mAbs

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Metastatic melanoma is an aggressive cancer with a poor prognostic, and the design of new targeted drugs to treat melanoma is a therapeutic challenge. A promising approach is to produce monoclonal antibodies (mAbs) against the endothelin B receptor (ETB), which is known to be overexpressed in melanoma and to contribute to proliferation, migration and vasculogenic mimicry associated with invasiveness of this cancer. We previously described rendomab-B1, a mAb produced by DNA immunization. It is endowed with remarkable characteristics in term of affinity, specificity and antagonist properties against human ETB expressed by the endothelial cells, but, surprisingly, had poor affinity for ETB expressed by melanoma cells. This characteristic strongly suggested the existence of a tumor-specific ETB form. In the study reported here, we identified a new mAb, rendomab-B4, which, in contrast to rendomab-B1, binds ETB expressed on UACC-257, WM-266-4 and SLM8 melanoma cells. Moreover, after binding to UACC-257 cells, rendomab-B4 is internalized and colocalizes with the endosomal protein EEA-1. Interestingly, rendomab-B4, despite its inability to compete with endothelin binding, is able to inhibit phospholipase C pathway and migration induced by endothelin. By contrast, rendomab-B4 fails to decrease ERK1/2 phosphorylation induced by endothelin, suggesting a biased effect on ETB. These particular properties make rendomab-B4 an interesting tool to analyze ETB-structure/function and a promising starting point for the development of new immunological tools in the field of melanoma therapeutics.

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“…Increasing evidence points to ETs as relevant mediators in tumor progression in a variety of malignancies (9). Melanoma cells express both ET A R and ET B R (10). Gene expression analysis (11) and immunophenotyping of human cutaneous melanoma (12) have recently identified ET B R as critical in the progression of this malignancy.…”

Section: Introductionmentioning

confidence: 99%