Faculty Collaboration Database

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

03/17/2007

Pubmed ID

17363508

DOI

10.1158/1535-7163.MCT-06-0665

Scopus ID

2-s2.0-34147168760 (requires institutional sign-in at Scopus site)   103 Citations

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.

Author List

Kunnimalaiyaan M, Vaccaro AM, Ndiaye MA, Chen H

MESH terms used to index this publication - Major topics in bold

Adjuvants, Immunologic
Animals
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