Epidermal growth factor increases lysophosphatidic acid production in human ovarian cancer cells: roles for phospholipase D2 and receptor transactivation.
Lysophosphatidic acid (LPA), is a lipid mediator that binds to G-protein coupled receptors. Epidermal growth factor (EGF), a polypeptide growth factor, binds to the EGF receptor (EGFR), a receptor tyrosine kinase. Both LPA and EGF induce responses in tumor cells that include proliferation, migration, metastasis, and induction of angiogenesis. LPA has the potential to act as an autocrine/paracrine factor and can transactivate the EGFR. This study explores the role of phospholipase D2 (PLD2) activation in LPA production, as well as cross-talk between EGF and LPA receptors. We demonstrate that EGF and LPA both stimulate production of LPA by OVCAR3 and SKOV3 human ovarian cancer cell lines. PD158780, an EGFR-selective tyrosine kinase inhibitor, blocks LPA production in response to both EGF and LPA in OVCAR3 and SKOV3 cells. Pertussis toxin, an inhibitor of LPA receptor signaling, inhibits LPA production in response to both EGF and LPA. Similar results were observed for the LPA receptor antagonist, Ki16425. Overexpression of PLD2 increases LPA production, while knockdown of PLD2 blocks EGF-induced LPA production. A phospholipase A2 (PLA2) inhibitor also blocks LPA- and EGF-induced LPA production. These results indicate that EGF stimulates LPA production in a manner that requires PLD2, and suggest that cross-talk can occur bidirectionally between EGF and LPA receptors.
Snider
Ashley J
AJ
Department of Pharmaceutical Sciences, Washington State Univ., Pullman, WA 99164-6534, USA.
Zhang
Zhihong
Z
Xie
Yuhuan
Y
Meier
Kathryn E
KE
D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008246:Lysophospholipids / Q000096:biosynthesis*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology*; D010739:Phospholipase D / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020239:Receptor Cross-Talk / Q000502:physiology; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection
D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D004815:Epidermal Growth Factor; D037342:Pertussis Toxin; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C105606:phospholipase D2; D010739:Phospholipase D; C032881:lysophosphatidic acid