Inactivation of glycogen synthase kinase-3beta, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells.
Glycogen synthase kinase-3beta (GSK-3beta) is an important regulator of cell proliferation and survival. Conflicting observations have been reported regarding the regulation of GSK-3beta and extracellular signal-regulated kinase (ERK1/2) in cancer cells. In this study, we found that raf-1 activation in human medullary thyroid cancer cells, TT cells, resulted in phosphorylation of GSK-3beta. Inactivation of GSK-3beta in TT cells with well-known GSK-3beta inhibitors such as lithium chloride (LiCl) and SB216763 is associated with both growth suppression and a significant decrease in neuroendocrine markers such as human achaete-scute complex-like 1 and chromogranin A. Growth inhibition by GSK-3beta inactivation was found to be associated with cell cycle arrest due to an increase in the levels of cyclin-dependent kinase inhibitors such as p21, p27, and p15. Additionally, LiCl-treated TT xenograft mice had a significant reduction in tumor volume compared with those treated with control. For the first time, we show that GSK-3beta is a key downstream target of the raf-1 pathway in TT cells. Also, our results show that inactivation of GSK-3beta alone is sufficient to inhibit the growth of TT cells both in vitro and in vivo.
Kunnimalaiyaan
Muthusamy
M
University of Wisconsin, H4/750 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA.
Vaccaro
Abram M
AM
Ndiaye
Mary A
MA
Chen
Herbert
H
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018276:Carcinoma, Medullary / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D053379:Chromogranin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells / Q000187:drug effects; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D023041:Xenograft Model Antitumor Assays
D000276:Adjuvants, Immunologic; D053379:Chromogranin A; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007211:Indoles; D008301:Maleimides; C417521:SB 216763; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D019908:Proto-Oncogene Proteins c-raf; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride