Inactivation of glycogen synthase kinase-3beta, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells. Mol Cancer Ther 2007 Mar;6(3):1151-8
Date
03/17/2007Pubmed ID
17363508DOI
10.1158/1535-7163.MCT-06-0665Scopus ID
2-s2.0-34147168760 (requires institutional sign-in at Scopus site) 100 CitationsAbstract
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.
Author List
Kunnimalaiyaan M, Vaccaro AM, Ndiaye MA, Chen HMESH terms used to index this publication - Major topics in bold
Adjuvants, ImmunologicAnimals
Apoptosis
Carcinoma, Medullary
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Chromogranin A
Cyclin D1
Cyclin-Dependent Kinase Inhibitor p15
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Humans
Indoles
Lithium Chloride
Maleimides
Mice
Mice, Nude
NIH 3T3 Cells
Phosphorylation
Proto-Oncogene Proteins c-raf
Signal Transduction
Thyroid Neoplasms
Xenograft Model Antitumor Assays