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Research Articles: Therapeutics, Targets, and Development

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

Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin and the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin

Requests for reprints: Herbert Chen, University of Wisconsin, H4/750 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792. Phone: 608-263-1387; Fax: 608-263-7652. E-mail: chen{at}surgery.wisc.edu

Abstract

Glycogen synthase kinase-3ß (GSK-3ß) is an important regulator of cell proliferation and survival. Conflicting observations have been reported regarding the regulation of GSK-3ß 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-3ß. Inactivation of GSK-3ß in TT cells with well-known GSK-3ß 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-3ß 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-3ß is a key downstream target of the raf-1 pathway in TT cells. Also, our results show that inactivation of GSK-3ß alone is sufficient to inhibit the growth of TT cells both in vitro and in vivo. [Mol Cancer Ther 2007;6(3):1151–8]

Grant support: Research Scholars Grant from the American Cancer Society, NIH grants DK063015, DK064735, DK066169, CA109053, the George H.A. Clowes, Jr., Memorial Research Career Development Award of the American College of Surgeons, Carcinoid Cancer Foundation (H. Chen), and the Robert Draper Technology Innovation Award (M. Kunnimalaiyaan).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/27/06; revised 12/20/06; accepted 2/ 1/07.

This article has been cited by other articles:

				R. S. Sippel, M. Kunnimalaiyaan, and H. Chen Current Management of Medullary Thyroid Cancer Oncologist, May 1, 2008; 13(5): 539 - 547. [Abstract] [Full Text] [PDF]