Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells

L. Rosanò, M. Varmi, D. Salani, V. Di Castro, F. Spinella, P. G. Natali, A. Bagnato

Research output: Contribution to journalArticle

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Abstract

Endothelin-1 (ET-1) is present at high concentrations in ovarian cancer ascites and is overexpressed in primary and metastatic ovarian carcinoma. In these cells, ET-1 acts as an autocrine mitogenic and angiogenic factor selectively through the ETA receptor (ETAR). We investigated at mRNA and protein levels whether ET-1 could affect the expression and activation of metastasis-related proteinases and whether this process was associated with ovarian tumor cell invasion. ELISA, gelatin zymography, Western blot, and reverse transcription-PCR analyses demonstrated that in two ovarian carcinoma cell lines (HEY and OVCA 433), the expression of matrix metalloproteinase (MMP) -2, -9, -3, -7, and -13 was up-regulated and activated by ET-1. Moreover we observed that ET-1 was able to enhance the secretion and activation of membrane-type metalloproteinase-1, a critical mediator of invasiveness. The secretion of tissue inhibitor of metalloproteinase-1 and -2 was decreased by ET-1, which increased the net MMP/tissue inhibitor of metalloproteinase balance and the gelatinolytic capacity. In addition, ET-1 induced overexpression of urokinase-type plasminogen activator, its receptor, and plasminogen activator inhibitor type-1 and -2. Finally, we demonstrated that, in HEY and OVCA 433 cells, ET-1 dose-dependently increased migration and MMP-dependent invasion through Matrigel. BQ123, an antagonist of the ETAR, inhibited the ET-1-induced tumor protease activity and subsequent increase in cell migration and invasion. These findings demonstrate that ET-1 promotes ovarian carcinoma cell invasion, acting through the ETAR by up-regulating secretion and activation of multiple tumor proteinases. Therefore, ET-1 may represent a key component of more aggressive ligand-induced invasiveness of ovarian carcinoma.

Original languageEnglish
Pages (from-to)8340-8346
Number of pages7
JournalCancer Research
Volume61
Issue number22
Publication statusPublished - Nov 15 2001

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Endothelin-1
Peptide Hydrolases
Carcinoma
Neoplasms
Plasminogen Activator Inhibitor 2
Urokinase Plasminogen Activator Receptors
Tissue Inhibitor of Metalloproteinases
Endothelin A Receptors
Tissue Inhibitor of Metalloproteinase-2
Tissue Inhibitor of Metalloproteinase-1
Matrix Metalloproteinase Inhibitors
Angiogenesis Inducing Agents
Matrix Metalloproteinase 2
Plasminogen Activator Inhibitor 1
Matrix Metalloproteinase 9
Metalloproteases
Gelatin
Matrix Metalloproteinases
Ascites
Ovarian Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Rosanò, L., Varmi, M., Salani, D., Di Castro, V., Spinella, F., Natali, P. G., & Bagnato, A. (2001). Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. Cancer Research, 61(22), 8340-8346.

Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. / Rosanò, L.; Varmi, M.; Salani, D.; Di Castro, V.; Spinella, F.; Natali, P. G.; Bagnato, A.

In: Cancer Research, Vol. 61, No. 22, 15.11.2001, p. 8340-8346.

Research output: Contribution to journalArticle

Rosanò, L, Varmi, M, Salani, D, Di Castro, V, Spinella, F, Natali, PG & Bagnato, A 2001, 'Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells', Cancer Research, vol. 61, no. 22, pp. 8340-8346.
Rosanò L, Varmi M, Salani D, Di Castro V, Spinella F, Natali PG et al. Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. Cancer Research. 2001 Nov 15;61(22):8340-8346.
Rosanò, L. ; Varmi, M. ; Salani, D. ; Di Castro, V. ; Spinella, F. ; Natali, P. G. ; Bagnato, A. / Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. In: Cancer Research. 2001 ; Vol. 61, No. 22. pp. 8340-8346.
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