Regulation of human thyroid follicular cell function by inhibition of vascular endothelial growth factor receptor signalling.
The potential autocrine role of human thyroid vascular endothelial growth factors (VEGFs) was examined using the VEGF receptor (VEGFR) inhibitor, ZM306416HCl. ZM306416HCl reduced VEGFR2 phosphorylation and inhibited endogenous, steady-state levels of p42/44 MAPK phosphorylation. It potently inhibited the secretion of plasminogen activators (PA) and increased (125)I uptake. Cell survival was compromised but rescued with insulin and TSH. Although the EGF receptor remained responsive to challenge by EGF in p42/44 MAPK assays, stimulatory effects of EGF on PA production were prevented by ZM306416HCl and those of protein kinase C stimulator, TPA reduced. In assays of (125)I uptake, ZM306416HCl prevented the inhibitory effects of EGF but not those of TPA. We conclude that autocrine VEGF may modulate thyroid function and that VEGFR inhibition increases iodide uptake and decreases PA production through regulation of p42/44 MAPK phosphorylation. VEGFR inhibition may have effects on thyroid function which may contribute to "off target" effects in clinical trials.
School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK. R.Susarla@bham.ac.uk
Radhika
R
Susarla
John C
JC
Watkinson
Margaret C
MC
Eggo
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D004815:Epidermal Growth Factor; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D015609:Organotechnetium Compounds; D010766:Phosphorylation / Q000187:drug effects; D010960:Plasminogen Activators / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013961:Thyroid Gland / Q000378:metabolism*; D013972:Thyrotropin / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C575425:(4-(4'-chloro-2'-fluoro)phenylamino)-6,7-dimethylquinazoline; D007328:Insulin; D015609:Organotechnetium Compounds; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C532955:technetium 99m (2-mercaptopyridine N-oxide)(N-ethoxyethyl-N,N-bis(2-(bis(3-methoxypropyl)phosphino)ethyl)amine); D004815:Epidermal Growth Factor; D013972:Thyrotropin; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010960:Plasminogen Activators; D013755:Tetradecanoylphorbol Acetate