Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible factor-1α in human melanoma cells

Francesca Spinella, Laura Rosanò, Valeriana Di Castro, Samantha Decandia, Maria Rita Nicotra, Pier Giorgio Natali, Anna Bagnato

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Endothelin (ET) B receptor (ETBR), which is overexpressed in human cutaneous melanomas, promotes tumorigenesis upon activation by ET-1 or ET-3, thus representing a potential novel therapeutic target. Hypoxia-inducible factor-1α (HIF-1α) is the transcriptional factor that conveys signaling elicited by hypoxia and growth factor receptors. Here, we investigated the interplay between ET axis and hypoxia in primary and metastatic melanoma cell lines. We report that under normoxic conditions, ETBR activation by ET-1/ET-3 enhances vascular endothelial growth factor (VEGF) up-regulation, cyclooxygenase (COX)-1/COX-2 protein expression and COX-2 promoter activity, prostaglandin E2 (PGE2) production, and do so to a greater extent under hypoxia. Moreover, COX-1/COX-2 inhibitors block ET-induced PGE2 and VEGF secretion, matrix metalloproteinase (MMP) activation, and cell invasion, indicating that both enzymes function as downstream mediators of ET-induced invasive properties. The ETBR selective antagonist BQ788 or transfection with ETBR small interfering RNA (siRNA) block the ET-mediated effects. ETs also increase HIF-1α expression under both normoxic and hypoxic conditions and its silencing by siRNA desensitizes COX-2 transcriptional activity, PGE2 and VEGF production, and MMP activation in response to ET-3, implicating, for the first time, HIF-1α/COX as downstream targets of ETBR signaling leading to invasiveness. In melanoma xenografts, specific ETBR antagonist suppresses tumor growth, neovascularization, and invasiveness-related factors. Collectively, these results identify a new mechanism whereby ET-1/ET-3/ET BR axis can promote and interact with the HIF-1α-dependent machinery to amplify the COX-mediated invasive behavior of melanoma. New therapeutic strategies using specific ETBR antagonist could provide an improved approach to the treatment of melanoma by inhibiting tumor growth and progression.

Original languageEnglish
Pages (from-to)1725-1734
Number of pages10
JournalCancer Research
Volume67
Issue number4
DOIs
Publication statusPublished - Feb 15 2007

Fingerprint

Endothelin-3
Hypoxia-Inducible Factor 1
Endothelins
Endothelin-1
Melanoma
Cyclooxygenase 2
Dinoprostone
Vascular Endothelial Growth Factor A
Endothelin B Receptors
Cyclooxygenase 1
Prostaglandin-Endoperoxide Synthases
Matrix Metalloproteinases
Small Interfering RNA
Endothelin A Receptors
Growth Factor Receptors
Cyclooxygenase 2 Inhibitors
Growth
Heterografts
Transfection
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible factor-1α in human melanoma cells. / Spinella, Francesca; Rosanò, Laura; Di Castro, Valeriana; Decandia, Samantha; Nicotra, Maria Rita; Natali, Pier Giorgio; Bagnato, Anna.

In: Cancer Research, Vol. 67, No. 4, 15.02.2007, p. 1725-1734.

Research output: Contribution to journalArticle

Spinella, Francesca ; Rosanò, Laura ; Di Castro, Valeriana ; Decandia, Samantha ; Nicotra, Maria Rita ; Natali, Pier Giorgio ; Bagnato, Anna. / Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible factor-1α in human melanoma cells. In: Cancer Research. 2007 ; Vol. 67, No. 4. pp. 1725-1734.
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AU - Spinella, Francesca

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AU - Nicotra, Maria Rita

AU - Natali, Pier Giorgio

AU - Bagnato, Anna

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