GSK3β Signaling in Medullary Thyroid Cancer
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Medullary thyroid cancer (MTC) is a neuroendocrine tumor derived from the calcitonin-producing thyroid C-cells and accounts for 3-5% of cases of thyroid cancer. While surgery is the only potentially curative therapy for patients with MTC, almost all patients will have persistent or recurrent disease after total thyroidectomy and central lymph node dissection. Moreover, there is no effective alternative to treat many of the debilitating symptoms associated with incurable MTC such as airway obstruction, flushing, abdominal pain and diarrhea. We have shown that activation of raf-1 through inhibition of GSK3β markedly suppresses cellular growth and reduces hormone secretion in human MTC cells in vitro and in vivo. In this proposal, we will explore the potential to utilize GSK3β inhibitors such as lithium to improve surgical outcomes for patient with metastatic MTC. In the first aim, we will develop 2 animal models of recurrent/persistent MTC to determine if GSK3β inhibitors will inhibit tumor growth and suppress hormone production in vivo. In the second aim, we plan to characterize a large number of human thyroid tumor samples, including MTC, and normal thyroid tissue for expression of raf-1 and GSK3β signaling pathway members. The data from these analyses will help predict which patients may be more likely to respond to lithium and other GSK inhibiting compounds. In the third aim, we will delineate the role of GSK3β in raf-1-mediated growth suppression and hormone inhibition. We have found that raf-1 activation also results in an increase in phosphorylated, inactive GSK3β, and that treatment of MTC cells with GSK3β inhibitors, such as lithium chloride and SB216763, can recapitulate the effects of raf-1. We will determine whether or not raf-1-mediated growth and hormone suppression is dependent upon GSK3β inhibition, and if GSK3β is the main downstream target of raf-1. In summary, the studies in this proposal represent a novel approach to understanding the biology of MTC, and may provide new insights to treating and palliating this disease.
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General Surgery
University of Wisconsin Department of Surgery
First published: 07/15/02 Last updated: 11/23/09 webmaster@surgery.wisc.edu
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