Inactivation of glycogen synthase kinase-3beta, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells

• Published in: Molecular cancer therapeutics Vol. 6; no. 3; pp. 1151 - 1158
• Main Authors: Kunnimalaiyaan, Muthusamy, Vaccaro, Abram M, Ndiaye, Mary A, Chen, Herbert
• Format: Journal Article
• Language: English
• Published: United States 01.03.2007
• Subjects: Adjuvants, Immunologic - pharmacology; Animals; Apoptosis - drug effects; Apoptosis - physiology; Carcinoma, Medullary - enzymology; Carcinoma, Medullary - pathology; Carcinoma, Medullary - prevention & control; Cell Cycle - drug effects; Cell Cycle - physiology; Cell Line, Tumor - drug effects; Cell Line, Tumor - metabolism; Cell Proliferation - drug effects; Chromogranin A - metabolism; Cyclin D1 - metabolism; Cyclin-Dependent Kinase Inhibitor p15 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Humans; Indoles - pharmacology; Lithium Chloride - pharmacology; Maleimides - pharmacology; Mice; Mice, Nude; NIH 3T3 Cells - drug effects; Phosphorylation; Proto-Oncogene Proteins c-raf - genetics; Proto-Oncogene Proteins c-raf - metabolism; Signal Transduction - drug effects; Thyroid Neoplasms - enzymology; Thyroid Neoplasms - pathology; Thyroid Neoplasms - prevention & control; Xenograft Model Antitumor Assays
• ISSN: 1535-7163

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.