Translational implications of nongenomic actions of thyroid hormone initiated at its integrin receptor

Abstract

receptor on integrin ␣v␤3 that mediates cell surface-initiated nongenomic actions of thyroid hormone on tumor cell proliferation and on angiogenesis has been described. Transduction of the hormone signal into these recently recognized proliferative effects is by extracellular-regulated kinases 1/2 (ERK1/2). Other nongenomic actions of the hormone may be transduced by phosphatidylinositol 3-kinase (PI3K) and are initiated in cytoplasm or at the cell surface. PI3K-mediated effects are important to angiogenesis or other recently appreciated cell functions but apparently not to tumor cell division. For those actions of thyroid hormone [L-thyroxine (T4) and 3,3Ј-5-triiodo-L-thyronine (T3)] that begin at the integrin receptor, tetraiodothyroacetic acid (tetrac) is an inhibitor of and probe for the participation of the receptor in downstream intracellular events. In addition, tetrac has actions initiated at the integrin receptor that are unrelated to inhibition of the effects of T 4 and T3 but do involve gene transcription in tumor cells. Discussed here are the implications of translating these nongenomic mechanisms of thyroid hormone analogs into clinical cancer cell biology, tumor-related angiogenesis, and modulation of angiogenesis that is not related to cancer.

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

“…[47][48][49][50][51] Analysis of the promoters of PKR-and ER-mediated stress genes modulated by T3 did not find the presence of classical THR binding sequences, indicating that genomic mechanisms may not be involved in their induction by T3. In addition, induction of these pathways at nonphysiological concentrations of T3 and the expression of nonfunctional THR in HeLa cells 28 provide additional evidence that T3 modulates gene expression by nongenomic mechanisms that do not involve the binding of T3 to THR.…”

“…The nongenomic effects of T3 have been defined in a number of previous reports. [48][49][50][51] The effect of T3 on the activation of PKR, a central player that links innate immune response with stress response pathways, is as striking as its ability to induce the expression of ERresponse genes, phosphorylation of IRE1α, and induction of XBP1 splicing. These effects are consistent with T3-induced ISR pathways that lead to PKR activation, eIF2α phosphorylation, SG formation, and activation of ER stress pathways.…”

Integrin-Mediated Actions of Thyroid Hormone Analogues on Tumor Cell Chemosensitivity, Integrin-Growth Factor Receptor Crosstalk and Inflammatory Gene Expression

“…A thyroid hormone on plasma membrane integrin v3 initiates the actions of the hormone and certain analogues on angiogenesis Davis et al, 2009), on tumor cell proliferation (Rebbaa, 2008;Yalcin, Bharali et al, 2010;Yalcin et al, 2010;Meng et al, 2011) and on cancer cell radiosensitivity Hercbergs et al, 2011). These effects are initiated nongenomically, i.e., are independent of the classical nuclear receptor for thyroid hormone (TR) (Cheng et al, 2010), and may have downstream intracellular consequences that involve specific protein trafficking (Cao et al, 2009) and modulation of expression of specific genes involved in cancer cell survival pathways.…”

Design, synthesis, and biological evaluation of bifunctional thyrointegrin inhibitors: new anti-angiogenesis analogs

“…Several other reports [35][36][37][38] have described the effects of thyroid hormone analogs on integrin αVβ3, thyroid hormone receptor, and membrane Na + /H + anti-porter ion pumps, revealing a complex relationship between thyroid hormone and nuclear events that underlie important cellular and tissue processes, including angiogenesis and tumour cell proliferation. The thyroid hormone analogs, 2-ammonium-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]-propionate (T 3 ) and 2-ammonium-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3-, 5-diiodophenyl] propionate (T 4 ), have been shown to induce angiogenesis 39,40 , while the metabolic degradation product of thyroid hormone, tetra-iodothyroacetic acid (tetrac), inhibits angiogenesis in the chick chorioallantoic membrane (CAM) and other angiogenesis models ( Figure 1) [41][42][43][44][45] .…”