title: Thyroid hormone and anti-apoptosis in tumor cells.
abstract: The principal secretory product of the thyroid gland, L-thyroxine (T4), is anti-apoptotic at physiological concentrations in a number of cancer cell lines. Among the mechanisms of anti-apoptosis activated by the hormone are interference with the Ser-15 phosphorylation (activation) of p53 and with TNFα/Fas-induced apoptosis. The hormone also decreases cellular abundance and activation of proteolytic caspases and of BAX and causes increased expression of X-linked inhibitor of apoptosis (XIAP). The anti-apoptotic effects of thyroid hormone largely are initiated at a cell surface thyroid hormone receptor on the extracellular domain of integrin αvβ3 that is amply expressed and activated in cancer cells. Tetraiodothyroacetic acid (tetrac) is a T4 derivative that, in a model of resveratrol-induced p53-dependent apoptosis in glioma cells, blocks the anti-apoptotic action of thyroid hormone, permitting specific serine phosphorylation of p53 and apoptosis to proceed. In a nanoparticulate formulation limiting its action to αvβ3, tetrac modulates integrin-dependent effects on gene expression in human cancer cell lines that include increased expression of a panel of pro-apoptotic genes and decreased transcription of defensive anti-apoptotic XIAP and MCL1 genes. By a variety of mechanisms, thyroid hormone (T4) is an endogenous anti-apoptotic factor that may oppose chemotherapy-induced apoptosis in αvβ3-expressing cancer cells. It is possible to decrease this anti-apoptotic activity pharmacologically by reducing circulating levels of T4 or by blocking effects of T4 that are initiated at αvβ3.
authors.affiliation: PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei, Taiwan.|Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Stanford University, Palo Alto, CA, USA.
authors.forename: Gennadi V
authors.initials: GV
authors.lastname: Glinsky
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.|Department of Medicine, Albany Medical College, Albany, NY, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects*; D013974:Thyroxine / Q000378:metabolism / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020169:Caspases; D013974:Thyroxine
keywords: apoptosis; integrin αvβ3; resveratrol; tetrac; thyroid hormone