Paul J. Davis
Albany Medical College, USA
Title: Anti-Apoptotic Actions of Thyroid Hormone in Cancer Cells may limit Effectiveness of Chemotherapy
Biography
Biography: Paul J. Davis
Abstract
Thyroid hormone as L-thyroxine (T4) is anti-apoptotic at physiological concentrations in a number of cancer cell lines. Among the mechanisms of anti-apoptosis activated by T4 are interference with Ser-15 phosphorylation (activation) of p53 and with TNFï¡/Fas-induced apoptosis, as well as decreased cellular abundance of caspases and of BAX. Such actions of T4 may oppose pharmaceutical anti-apoptotic strategies. The anti-apoptotic effects of thyroid hormone largely are initiated at a cell surface thyroid hormone receptor on integrin ï¡vï¢3. The integrin is amply expressed and activated in cancer cells, but not in nonmalignant, nondividing cells. Nanoparticulate tetraiodothyroacetic acid (Nanotetrac) opposes actions of thyroid hormone initiated at ï¡vï¢3 (PJ Davis, Ann Rev Pharmacol Toxicol 51:99-115, 2011). We have studied the effects of Nanotetrac (10-7 M) in vitro on expression of a panel of apoptosis-relevant cancer cell genes in human breast cancer MDA-MB-231 (AB Glinskii et al., Cell Cycle 8:3562-3570, 2009) and human medullary thyroid carcinoma (mTC, CRL-1803) (M Yalcin et al., J Clin Endocrinol Metab 95:1972-1980, 2010) cell lines. CASP2, MCL2L14, DFFA, BAD and Bcl-Xs are pro-apoptotic genes whose expression was stimulated by Nanotetrac; XIAP and MCL1 are anti-apoptotic genes and their transcription in tumor cells was downregulated by Nanotetrac. Nanotetrac blocked the anti-apoptotic action of thyroid hormone in a stilbene-induced model of apoptosis in glioma cells. Thus, thyroid hormone (T4) is an endogenous anti-apoptotic factor that may oppose chemotherapy-induced apoptosis in ï¡vï¢3-expressing cancer cells. These actions of T4 have been blocked in vitro by Nanotetrac and rationalize medical induction of euthyroid hypothyroxinemia. \\r\\n\\r\\n
