Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway

Veronica C. Estrella, Astrid M. Eder, Shuying Liu, Terri B. Pustilnik, Fazal H. Tabassam, Francois X. Claret, Gary E. Gallick, Gordon Mills, Jon R. Wiener

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Lysophosphatidic acid (LPA) is an important intercellular signaling molecule involved in a myriad of biological responses. Elevated concentrations of LPA are present in the ascites and plasma of ovarian cancer patients suggesting a role for LPA in the pathophysiology of ovarian cancer. We have demonstrated previously that oleoyl (18:1) LPA at concentrations present in ascites induces the secretion of urokinase plasminogen activator (uPA) from ovarian cancer cells, possibly linking LPA to cellular invasion. In this study we sought to elucidate which signaling pathway(s) are involved in LPA-mediated secretion of uPA from ovarian cancer cells. Specific inhibitors were utilized to determine if interference with the p38MAPK, p42/44MAPK, and PI3K pathways functionally blocked LPA-mediated uPA secretion. LPA stimulation of ovarian cancer cells markedly increased the phosphorylation and activity of p38MAPK, p42/p44MAPK, and PI3K. Both tyrosine phosphorylation and Src kinase activity were required for optimal activation of signaling by LPA including phosphorylation of p38MAPK. Inhibition of p38MAPK signaling by SB202190 completely abrogated LPA-induced uPA secretion, while inhibition of the p42/44MAPK or PI3K pathways with PD98059 or wortmannin and LY294002, respectively, decreased but did not completely block uPA secretion. In contrast, inhibitors of phospholipase D or the p70S6 kinase pathway did not alter LPA-induced uPA secretion. Further, tyrosine phosphorylation and functional Src were required for optimal uPA secretion. Finally, LPA induces uPA secretion from ovarian cancer cells predominantly through the LPA2 receptor, with LPA3 contributing to this process. These results indicate that the p38MAPK signaling pathway is required for optimal LPA-dependent uPA secretion from ovarian cancer cells.

Original languageEnglish (US)
Pages (from-to)441-449
Number of pages9
JournalInternational Journal of Oncology
Volume31
Issue number2
StatePublished - Aug 1 2007
Externally publishedYes

Fingerprint

Plasminogen Activators
Urokinase-Type Plasminogen Activator
Ovarian Neoplasms
Phosphatidylinositol 3-Kinases
Phosphorylation
Ascites
lysophosphatidic acid
Lysophosphatidic Acid Receptors
Phospholipase D
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
src-Family Kinases
Tyrosine
Phosphotransferases

Keywords

  • Lysophosphatidic
  • Ovarian
  • p38
  • Src
  • Urokinase plasminogen activator

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Estrella, V. C., Eder, A. M., Liu, S., Pustilnik, T. B., Tabassam, F. H., Claret, F. X., ... Wiener, J. R. (2007). Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway. International Journal of Oncology, 31(2), 441-449.

Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway. / Estrella, Veronica C.; Eder, Astrid M.; Liu, Shuying; Pustilnik, Terri B.; Tabassam, Fazal H.; Claret, Francois X.; Gallick, Gary E.; Mills, Gordon; Wiener, Jon R.

In: International Journal of Oncology, Vol. 31, No. 2, 01.08.2007, p. 441-449.

Research output: Contribution to journalArticle

Estrella, VC, Eder, AM, Liu, S, Pustilnik, TB, Tabassam, FH, Claret, FX, Gallick, GE, Mills, G & Wiener, JR 2007, 'Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway', International Journal of Oncology, vol. 31, no. 2, pp. 441-449.
Estrella VC, Eder AM, Liu S, Pustilnik TB, Tabassam FH, Claret FX et al. Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway. International Journal of Oncology. 2007 Aug 1;31(2):441-449.
Estrella, Veronica C. ; Eder, Astrid M. ; Liu, Shuying ; Pustilnik, Terri B. ; Tabassam, Fazal H. ; Claret, Francois X. ; Gallick, Gary E. ; Mills, Gordon ; Wiener, Jon R. / Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway. In: International Journal of Oncology. 2007 ; Vol. 31, No. 2. pp. 441-449.
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abstract = "Lysophosphatidic acid (LPA) is an important intercellular signaling molecule involved in a myriad of biological responses. Elevated concentrations of LPA are present in the ascites and plasma of ovarian cancer patients suggesting a role for LPA in the pathophysiology of ovarian cancer. We have demonstrated previously that oleoyl (18:1) LPA at concentrations present in ascites induces the secretion of urokinase plasminogen activator (uPA) from ovarian cancer cells, possibly linking LPA to cellular invasion. In this study we sought to elucidate which signaling pathway(s) are involved in LPA-mediated secretion of uPA from ovarian cancer cells. Specific inhibitors were utilized to determine if interference with the p38MAPK, p42/44MAPK, and PI3K pathways functionally blocked LPA-mediated uPA secretion. LPA stimulation of ovarian cancer cells markedly increased the phosphorylation and activity of p38MAPK, p42/p44MAPK, and PI3K. Both tyrosine phosphorylation and Src kinase activity were required for optimal activation of signaling by LPA including phosphorylation of p38MAPK. Inhibition of p38MAPK signaling by SB202190 completely abrogated LPA-induced uPA secretion, while inhibition of the p42/44MAPK or PI3K pathways with PD98059 or wortmannin and LY294002, respectively, decreased but did not completely block uPA secretion. In contrast, inhibitors of phospholipase D or the p70S6 kinase pathway did not alter LPA-induced uPA secretion. Further, tyrosine phosphorylation and functional Src were required for optimal uPA secretion. Finally, LPA induces uPA secretion from ovarian cancer cells predominantly through the LPA2 receptor, with LPA3 contributing to this process. These results indicate that the p38MAPK signaling pathway is required for optimal LPA-dependent uPA secretion from ovarian cancer cells.",
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