Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells

Terri B. Pustilnik, Veronica Estrella, Jon R. Wiener, Muling Mao, Astrid Eder, Mary Anne V Watt, Robert C. Bast, Gordon Mills

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

Lysophosphatidic acid (LPA) is present at high concentrations in ascites from ovarian cancer patients and has potent mitogenic properties in vitro. Urokinase plasminogen activator (uPA), a critical component of the metastatic cascade, is also found at high concentrations in ovarian ascites and ovarian cancers, and the levels of uPA correlate inversely with prognosis. Because LPA stimulates the invasion of both hepatoma and lung cell lines, we investigated whether LPA could induce uPA secretion by ovarian epithelial cells and whether this process was associated with malignant transformation of ovarian epithelial cells. As indicated by zymography and Western blotting, physiologically relevant concentrations of LPA equivalent to those present in ovarian cancer ascites stimulated uPA secretion in the ovarian cancer cell lines OVCAR-3, SKOV-3, OVCA 429, OVCA 432, and OVCA 433, but not from established normal ovarian epithelial (NOE) cells as indicated by normal epithelial cell lines NOE 033 and NOE 035 or from SV40 large T antigen- immortalized normal epithelial cell lines IOSE 29 and IOSE 80. 18:1 LPA, but not 18:0 LPA, 16:0 LPA, or lysophosphatidylcholine, induced uPA secretion, concordant with previous studies of LPA receptor selectivity. Expression of the edg-2 LPA receptor was not consistently different between normal epithelial cell lines and ovarian cancer cell lines. In contrast, expression of the edg-4 LPA receptor was markedly increased in ovarian cancer cell lines as compared with NOE cell lines, raising the possibility that the edg-4 LPA receptor contributes to the ability of ovarian cancer cells but not NOE cells to produce uPA in response to LPA. LPA induced a consistent increase in uPA promoter activity and mRNA levels, suggesting that increased uPA production is, at least in part, transcriptional. Malignant transformation may alter LPA-induced cell activation by altering the pattern of LPA receptors present and may possibly lead to more aggressive behavior by up-regulating LPA- mediated uPA secretion and stimulating extracellular stromal breakdown and invasion.

Original languageEnglish (US)
Pages (from-to)3704-3710
Number of pages7
JournalClinical Cancer Research
Volume5
Issue number11
StatePublished - Nov 1 1999
Externally publishedYes

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Urokinase-Type Plasminogen Activator
Ovarian Neoplasms
Plasminogen Activators
Lysophosphatidic Acid Receptors
Epithelial Cells
Cell Line
Ascites
lysophosphatidic acid
Polyomavirus Transforming Antigens
Lysophosphatidylcholines
Viral Tumor Antigens
Hepatocellular Carcinoma
Western Blotting
Lung
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pustilnik, T. B., Estrella, V., Wiener, J. R., Mao, M., Eder, A., Watt, M. A. V., ... Mills, G. (1999). Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells. Clinical Cancer Research, 5(11), 3704-3710.

Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells. / Pustilnik, Terri B.; Estrella, Veronica; Wiener, Jon R.; Mao, Muling; Eder, Astrid; Watt, Mary Anne V; Bast, Robert C.; Mills, Gordon.

In: Clinical Cancer Research, Vol. 5, No. 11, 01.11.1999, p. 3704-3710.

Research output: Contribution to journalArticle

Pustilnik, TB, Estrella, V, Wiener, JR, Mao, M, Eder, A, Watt, MAV, Bast, RC & Mills, G 1999, 'Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells', Clinical Cancer Research, vol. 5, no. 11, pp. 3704-3710.
Pustilnik TB, Estrella V, Wiener JR, Mao M, Eder A, Watt MAV et al. Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells. Clinical Cancer Research. 1999 Nov 1;5(11):3704-3710.
Pustilnik, Terri B. ; Estrella, Veronica ; Wiener, Jon R. ; Mao, Muling ; Eder, Astrid ; Watt, Mary Anne V ; Bast, Robert C. ; Mills, Gordon. / Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells. In: Clinical Cancer Research. 1999 ; Vol. 5, No. 11. pp. 3704-3710.
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abstract = "Lysophosphatidic acid (LPA) is present at high concentrations in ascites from ovarian cancer patients and has potent mitogenic properties in vitro. Urokinase plasminogen activator (uPA), a critical component of the metastatic cascade, is also found at high concentrations in ovarian ascites and ovarian cancers, and the levels of uPA correlate inversely with prognosis. Because LPA stimulates the invasion of both hepatoma and lung cell lines, we investigated whether LPA could induce uPA secretion by ovarian epithelial cells and whether this process was associated with malignant transformation of ovarian epithelial cells. As indicated by zymography and Western blotting, physiologically relevant concentrations of LPA equivalent to those present in ovarian cancer ascites stimulated uPA secretion in the ovarian cancer cell lines OVCAR-3, SKOV-3, OVCA 429, OVCA 432, and OVCA 433, but not from established normal ovarian epithelial (NOE) cells as indicated by normal epithelial cell lines NOE 033 and NOE 035 or from SV40 large T antigen- immortalized normal epithelial cell lines IOSE 29 and IOSE 80. 18:1 LPA, but not 18:0 LPA, 16:0 LPA, or lysophosphatidylcholine, induced uPA secretion, concordant with previous studies of LPA receptor selectivity. Expression of the edg-2 LPA receptor was not consistently different between normal epithelial cell lines and ovarian cancer cell lines. In contrast, expression of the edg-4 LPA receptor was markedly increased in ovarian cancer cell lines as compared with NOE cell lines, raising the possibility that the edg-4 LPA receptor contributes to the ability of ovarian cancer cells but not NOE cells to produce uPA in response to LPA. LPA induced a consistent increase in uPA promoter activity and mRNA levels, suggesting that increased uPA production is, at least in part, transcriptional. Malignant transformation may alter LPA-induced cell activation by altering the pattern of LPA receptors present and may possibly lead to more aggressive behavior by up-regulating LPA- mediated uPA secretion and stimulating extracellular stromal breakdown and invasion.",
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