Role of TGF alpha stimulation of the ERK, PI3 kinase and PLC gamma pathways in ovarian cancer growth and migration.
The Epidermal Growth Factor Receptor (EGFR) and its structural relative erbB2 are frequently over-expressed in ovarian cancers and both are strongly associated with poor patient survival. To investigate the relative roles of these receptors in the regulation of cell growth and migration, a panel of ovarian carcinoma cell lines were stimulated with TGF alpha and NRG1beta. TGF alpha had a much greater influence on cell migration than NRG1beta where growth effects were equivalent. The extent of TGF alpha-stimulated migration on collagen in these assays could be associated with erbB2 expression levels. In addition, TGF alpha was found to stimulate activation of the ERK, PI3 kinase and PLC gamma pathways. Direct blockade of the TGF alpha-interacting receptor EGFR inhibited both cell growth and migration, as well as downstream signaling induced by the growth factor. Specific blockade of the downstream proteins MEK and PI3 kinase significantly affected TGF alpha-induced mitogenesis in the cell lines tested but had less impact upon migration. Conversely, inhibition of the PLC gamma pathway had little effect on cell growth but significantly decreased TGF alpha-driven migration. These results corroborate the likely importance of migration as well as growth in erbB receptor over-expressing ovarian cancers and directly implicate the roles of ERK and PI3 kinase in growth control, and PLC gamma in the regulation of migration in this disease.
Sewell
Jane M
JM
Cancer Research UK Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom.
Smyth
John F
JF
Langdon
Simon P
SP
D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism / Q000502:physiology; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051966:Phospholipase C gamma; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism*
D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D016211:Transforming Growth Factor alpha; D010738:Type C Phospholipases