Tyrosine kinase inhibitor STI571 enhances thyroid cancer cell motile response to Hepatocyte Growth Factor.
The Hepatocyte Growth Factor (HGF) and its receptor Met are physiological regulators of cell migration. HGF and Met have also been implicated in tumor progression and metastasis. We show here that the tyrosine kinase inhibitor STI571 has a stimulatory effect on HGF-induced migration and branching morphogenesis in thyroid cancer but not in primary or immortalized thyroid epithelial cells. These stimulatory effects of STI571 are observed at a concentration that is clinically relevant. The STI571-enhanced motile response can be correlated with an increase in the Met receptor tyrosine phosphorylation as well as ERK and Akt activation by HGF. Interestingly, one of the targets of STI571, namely the c-Abl tyrosine kinase, is activated by HGF and is recruited at the migrating edge of thyroid cancer cells. These data suggests that c-Abl and/or STI571-inhibited tyrosine kinases can negatively regulate the Met receptor to restrain the motile response in thyroid cancer cells.
Frasca
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Istituto di Medicina Interna, Malattie Endocrine e Del Metabolismo, Università di Catania, Ospedale Garibaldi, Piazza S. Maria di Gesù, 95123 Catania, Italy. segmeint@mbox.unict.it
Vigneri
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Vella
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Vigneri
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Wang
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JY
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005109:Extracellular Matrix; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009024:Morphogenesis; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D013961:Thyroid Gland / Q000166:cytology; D013964:Thyroid Neoplasms; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D016315:Proto-Oncogene Proteins c-abl; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases