title: Lysophosphatidic acid induces both EGFR-dependent and EGFR-independent effects on DNA synthesis and migration in pancreatic and colorectal carcinoma cells.
abstract: Lysophosphatidic acid (LPA) is a small glycerophospholipid ubiquitously present in tissues and plasma. It acts through receptors belonging to the G-protein-coupled receptor (GPCR) family, is involved in several biological processes, and is strongly implicated in different cancers. In this paper, we have investigated the effects of LPA on DNA synthesis and migration in a panel of pancreatic and colon cancer cells, with particular focus on the involvement of the epidermal growth factor (EGF) receptor (EGFR) in LPA-induced signaling. LPA stimulated DNA synthesis and/or migration in all the cell lines included in this study. In five of the six cell lines, LPA induced phosphorylation of the EGFR, and the effects on EGFR and Akt, and in some of the cells also ERK, were sensitive to the EGFR tyrosine kinase inhibitor gefitinib, strongly suggesting LPA-induced EGFR transactivation in these cells. In contrast, in one of the pancreatic carcinoma cell lines (Panc-1), we found no evidence of transactivation of the EGFR. In the pancreatic carcinoma cell lines where transactivation took place (BxPC3, AsPC1, HPAFII), gefitinib reduced LPA-induced DNA synthesis and/or migration. However, we also found evidence of transactivation in the two colon carcinoma cell lines (HT29, HCT116) although gefitinib did not inhibit LPA-induced DNA synthesis or migration in these cells. Taken together, the data indicate that in many gastrointestinal carcinoma cells, LPA uses EGFR transactivation as a mechanism when exerting such effects as stimulation of cell proliferation and migration, but EGFR-independent pathways may be involved instead of, or in concerted action with, the EGFR transactivation.
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057, Blindern, N-0316, Oslo, Norway. ingunhei@medisin.uio.no.
authors.forename: Ingun Heiene
authors.initials: IH
authors.lastname: Tveteraas
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057, Blindern, N-0316, Oslo, Norway.
authors.forename: Monica
authors.initials: M
authors.lastname: Aasrum
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057, Blindern, N-0316, Oslo, Norway.|Department of Oral Biology and Department of Paediatric Dentistry and Behavioural Science, Faculty of Dentistry, University of Oslo, Blindern, Oslo, Norway.
authors.forename: Ingvild Johnsen
authors.initials: IJ
authors.lastname: Brusevold
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057, Blindern, N-0316, Oslo, Norway.
authors.forename: John
authors.initials: J
authors.lastname: Ødegård
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057, Blindern, N-0316, Oslo, Norway.
authors.forename: Thoralf
authors.initials: T
authors.lastname: Christoffersen
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057, Blindern, N-0316, Oslo, Norway.
authors.forename: Dagny
authors.initials: D
authors.lastname: Sandnes
mesh_terms: D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology* / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: D008246:Lysophospholipids; D011799:Quinazolines; D004247:DNA; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C032881:lysophosphatidic acid; D000077156:Gefitinib
keywords: Colon cancer; EGFR transactivation; Lysophosphatidic acid (LPA); Pancreatic cancer