Rapid nongenomic effects of 3,5,3′-triiodo-L-thyronine on the intracellular pH of L-6 myoblasts are mediated by intracellular calcium mobilization and kinase pathways

L-T3 and L-T4 activated the Na+/H + exchanger of L-6 myoblasts, with a fast nongenomic mechanism, both in the steady state and when cells undergo acid loading with ammonium chloride. Monitored with the intracellular pH-sensitive fluorescent probe 2′,7′-bis(carboxyethyl)-5(6)-carboxyfluorescein, activation of the exchanger appeared to be initiated at the plasma membrane, because T 3-agarose reproduced the effect of L-T3, and triiodothyroacetic acid, a hormone analog previously shown to inhibit membrane actions of thyroid hormone, blocked the action of L-T3 on the exchanger. We show here for the first time that transduction of the hormone signal in this nongenomic response requires tyrosine kinase-dependent phospholipase C activation and two different signaling pathways: 1) mobilization of intracellular calcium, assessed by the fluorescent probe fura-2, through activation, of inositol tris-phosphate receptors and without contributions from extracellular calcium or ryanodine receptors; and 2) protein phosphorylation involving protein kinase C and MAPK (ERK1/2), as shown by the use of kinase inhibitors and by immunoblotting for activated kinases.Fil: D'Arezzo, Silvia. Università di Roma; ItaliaFil: Incerpi, Sandra. Università di Roma; ItaliaFil: Davis, Faith B.. Ordway Research Institute; Estados UnidosFil: Acconcia, Filippo. Università di Roma; ItaliaFil: Marino, Maria. Università di Roma; ItaliaFil: Farias, Ricardo Norberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Davis, Paul J.. Ordway Research Institute; Estados Unido

Thyroid hormone inhibition in L6 myoblasts of IGF-I-mediated glucose uptake and proliferation: New roles for integrin αvβ3

Thyroid hormones L-thyroxine (T4) and 3,3′,5-triiodo-L-thyronine (Se

Tetrac and NDAT Induce Anti-proliferation via Integrin αvβ3 in Colorectal Cancers With Different K-RAS Status

Colorectal cancer is a serious medical problem in Taiwan. New, effective therapeutic approaches are needed. The selection of promising anticancer drugs and the transition from pre-clinical investigations to clinical trials are often challenging. The deaminated thyroid hormone analog (tetraiodothyroacetic acid, tetrac) and its nanoparticulate analog (NDAT) have been shown to have anti-proliferative activity in vitro and in xenograft model of different neoplasms, including colorectal cancers. However, mechanisms involved in tetrac- and NDAT-induced anti-proliferation in colorectal cancers are incompletely understood. We have investigated possible mechanisms of tetrac and NDAT action in colorectal cancer cells, using a perfusion bellows cell culture system that allows efficient, large-scale screening for mechanisms of drug actions on tumor cells. Although integrin αvβ3 in K-RAS wild type colorectal cancer HT-29 cells was far less than that in K-RAS mutant HCT116 cells, HT-29 was more sensitive to both tetrac and NDAT. Results also indicate that both tetrac and NDAT bind to tumor cell surface integrin αvβ3, and the agents may have different mechanisms of anti-proliferation in colorectal cancer cells. K-RAS status appears to play an important role in drug resistance that may be encountered in treatment with this drug combination

Nongenomic Actions of Thyroid Hormones

Nongenomic actions of thyroid hormone do not require a direct interaction of 3,5,30-triiodo-L-thyronine (T3) with the transcriptionally active nuclear receptors TRα and TRβ. A rapid response time is a characteristic of many nongenomic actions; the onset of the majority of these effects is within minutes because the action is independent of gene expression and protein synthesis. While only T3 is able to generate a genomic response, the different nongenomic effects may be activated by either T3 or T4 or by other iodothyronine derivatives such as T2. In the last decade, the discovery of a large number of nongenomic actions of thyroid hormones has increasingly attracted the interest of researchers, and different specific binding sites or receptors for these hormones/messengers have now been described in several cellular compartments, including the external surface of the plasma membrane. The function of nongenomic effects of these hormones has mainly been considered to relate to homeostasis, such as actions on plasma membrane ion transporters or maintenance of the cytoskeleton, but recent evidence supports the existence of crosstalk between nongenomic and genomic effects of the hormone. Further examination of such crosstalk may reveal hitherto unappreciated mechanisms underlying global illnesses, such as cardiovascular diseases, inflammatory and immune diseases, and mechanisms of tumor cell function. Indeed, these new aspects have already improved our understanding of the contributions of nongenomic thyroid hormone actions to the regulation of cancer-related angiogenesis and to cancer cell survival pathways. In the present report, we provide a concise overview of the main observations that define the nongenomic actions of thyroid hormones and give a description of the state of the art