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

Academic Article

Abstract

  • Glycogen synthase kinase-3β (GSK-3β) is an important regulator of cell proliferation and survival. Conflicting observations have been reported regarding the regulation of GSK-3β 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-3β. Inactivation of GSK-3β in TT cells with well-known GSK-3β inhibitors such as lithium chloride (LiCI) 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-3β 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, LiCI-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-3β is a key downstream target of the raf-1 pathway in TT cells. Also, our results show that inactivation of GSK-3β alone is sufficient to inhibit the growth of TT cells both in vitro and in vivo. Copyright © 2007 American Association for Cancer Research.
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    Digital Object Identifier (doi)

    Author List

  • Kunnimalaiyaan M; Vaccaro AM; Ndiaye MA; Chen H
  • Start Page

  • 1151
  • End Page

  • 1158
  • Volume

  • 6
  • Issue

  • 3