Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway.
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 p38(MAPK), p42/44(MAPK), and PI3K pathways functionally blocked LPA-mediated uPA secretion. LPA stimulation of ovarian cancer cells markedly increased the phosphorylation and activity of p38(MAPK), p42/p44(MAPK), and PI3K. Both tyrosine phosphorylation and Src kinase activity were required for optimal activation of signaling by LPA including phosphorylation of p38(MAPK). Inhibition of p38(MAPK) signaling by SB202190 completely abrogated LPA-induced uPA secretion, while inhibition of the p42/44(MAPK) 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 p38(MAPK) signaling pathway is required for optimal LPA-dependent uPA secretion from ovarian cancer cells.
Estrella
Veronica C
VC
Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77225, USA.
Eder
Astrid M
AM
Liu
Shuying
S
Pustilnik
Terri B
TB
Tabassam
Fazal H
FH
Claret
Francois X
FX
Gallick
Gary E
GE
Mills
Gordon B
GB
Wiener
Jon R
JR
D001692:Biological Transport; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D010051:Ovarian Neoplasms / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D010739:Phospholipase D; D014568:Urokinase-Type Plasminogen Activator; C032881:lysophosphatidic acid