title: Dual contribution of MAPK and PI3K in epidermal growth factor-induced destabilization of thyroid follicular integrity and invasion of cells into extracellular matrix.
abstract: Normal thyrocytes grown as reconstituted follicles in collagen gel were evaluated for drug effects of small molecule kinase inhibitors on growth factor-induced cell migration in a 3D context. MEK inhibition by U0126 only partially antagonized EGF/serum-induced cell migration from the basal follicular surface into the matrix. Combined treatment with U0126 and LY294002, a PI3K blocker, was necessary to abolish migration. However, exposure to only LY294002 facilitated the response to EGF by breakdown of the original follicular structure. In the same time EGF promoted thyroid cell survival that was compromised by LY294002 in absence of EGF. Cells treated with EGF and LY294002 retained the ability to form follicles. The findings indicate that dual inhibition of MAPK and PI3K/AKT pathways is required to fully block matrix invasion of EGF-stimulated thyroid cells. Conversely, single drug treatment with PI3K inhibitor adversely promotes invasiveness probably by destabilizing the follicular epithelium.
authors.affiliation: Sahlgrenska Cancer Center (SCC), Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Ingeson-Carlsson
authors.affiliation: Sahlgrenska Cancer Center (SCC), Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden. Electronic address: mikael.nilsson@gu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013552:Swine; D013961:Thyroid Gland / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D046509:Tissue Culture Techniques
chemical_list: D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: EGF; EMT; MEK; Migration; PI3K; Thyroid