Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / pharmacology
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Carcinoma, Medullary / enzymology
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Carcinoma, Medullary / pathology
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Carcinoma, Medullary / prevention & control*
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Cell Cycle / drug effects
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Cell Cycle / physiology
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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Cell Proliferation / drug effects
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Chromogranin A / metabolism
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase Inhibitor p15 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Indoles / pharmacology*
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Lithium Chloride / pharmacology
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Maleimides / pharmacology*
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Mice
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Mice, Nude
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NIH 3T3 Cells / drug effects
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Phosphorylation
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Proto-Oncogene Proteins c-raf / genetics
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Proto-Oncogene Proteins c-raf / metabolism*
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Signal Transduction / drug effects
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Thyroid Neoplasms / enzymology
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Thyroid Neoplasms / pathology
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Thyroid Neoplasms / prevention & control*
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Xenograft Model Antitumor Assays
Substances
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Adjuvants, Immunologic
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Chromogranin A
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p21
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Indoles
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Maleimides
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SB 216763
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Cyclin D1
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Cyclin-Dependent Kinase Inhibitor p27
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Proto-Oncogene Proteins c-raf
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Glycogen Synthase Kinase 3
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Lithium Chloride