Integrin αvß3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells.

The interaction of lymphoid tumor cells with components of the extracellular matrix via integrin αvß3 allows tumor survival and growth. This integrin was demonstrated to be the membrane receptor for thyroid hormones (THs) in several tissues. We found that THs, acting as soluble integrin αvß3 ligands, activated growth-related signaling pathways in T-cell lymphomas (TCLs). Specifically, TH-activated αvß3 integrin signaling promoted TCL proliferation and angiogenesis, in part, via the upregulation of vascular endothelial growth factor (VEGF). Consequently, genetic or pharmacologic inhibition of integrin αvß3 decreased VEGF production and induced TCL cell death in vitro and in human xenograft models. In sum, we show that integrin αvß3 transduces prosurvival signals into TCL nuclei, suggesting a novel mechanism for the endocrine modulation of TCL pathophysiology. Targeting this mechanism could constitute an effective and potentially low-toxicity chemotherapy-free treatment of TCL patients.

Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells.

Thyroid hormones (THs) - 3,3',5-triiodo-L-thyronine (T3) and L-thyroxine (T4) - are important regulators of the metabolism and physiology of most normal tissues. Cytochrome P450 family 3A members are drug metabolizing enzymes involved in the activation and detoxification of several drugs. CYP3A4 is the major enzyme involved in the metabolism of chemotherapeutic drugs. In this work, we demonstrate that THs induce a significant increase in CYP3A4 mRNA levels, protein expression and metabolic activity through the membrane receptor integrin αvß3 and the activation of signalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4 modulation may act as an important regulator in the metabolism of doxorubicin (Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, no TH-mediated chemosensitivity to Doxo was observed. We also found that THs modulate these functions by activating the membrane receptor integrin αvß3. In addition, we showed that the thyroid status can modulate CYP450 mRNA levels in tumor and liver tissues, and the tumor volume in response to chemotherapy in vivo. In fact, Doxo treatment in hypothyroid mice was associated with lower tumors, displaying lower levels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYP enzymes were found in livers from Doxo treated hypothyroid mice respect to control. These results present a new mechanism by which TH could modulate chemotherapy response. These findings highlight the importance of evaluating thyroid status in patients during application of T-cell lymphoma therapeutic regimens.

Thyroid hormones-membrane interaction: reversible association of hormones with organized phospholipids with changes in fluidity and dipole potential.

Differential scanning calorimetry (DSC), mixed monomolecular layers and fluorescence spectroscopy techniques were applied to investigate the effect of thyroid hormones (THs) on the biophysical properties of model membranes. We found that both 3,3',5-triiodo-L-thyronine (T3) and 3,5,3',5'-tetraiodo-L-thyronine (T4) induce a broadening of the calorimetric main phase transition profile and reduce the transition enthalpy in liquid-crystalline state of dipalmitoylphosphatylcholine (DPPC) multilamellar vesicles. Tm changes from 41 °C to 40 °C compared to pure DPPC. When the experiments were done by adding THs to preformed multilamellar vesicles a second broader component in the DSC scan also appears at 20 min of incubation and becomes gradually more prominent with time, indicating a progressive alteration of lipid phase induced by THs. Analysis of surface pressure-molecular area isotherms in mixed monolayers of THs with either DPPC or 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) at air-water interface indicated a reduction in molecular area for THs/lipid mixtures at all surface pressures. A substantial decrease in surface potential in mixed lipid/THs monolayers at all surface pressures were observed for both phospholipids without affecting the mixed monolayer integrity. The data of mixed lipid/THs behavior support the establishment of lateral miscibility. Alterations of bidimensional liquid expanded→liquid condensed phase transition observed for DPPC/THs mixed monolayers are compatible with the changes observed in DSC. The transverse movement of THs and the decrease of dipole potential were also observed in single unilamellar vesicles by using appropriate fluorescent probes.

Molecular view by fourier transform infrared spectroscopy of the relationship between lactocin 705 and membranes: speculations on antimicrobial mechanism.

Lactocin 705 is a bacteriocin whose activity depends upon the complementation of two peptides, termed Lac705alpha and Lac705beta. Neither Lac705alpha nor Lac705beta displayed bacteriocin activity by itself when the growth of sensitive cells was monitored. To obtain molecular insights into the lactocin 705 mechanism of action, Fourier transform infrared spectroscopy was used to investigate the interactions of each peptide (Lac705alpha and Lac705beta) with dipalmitoylphosphatidylcholine liposomal membranes. Both peptides show the ability to interact with the zwitterionic membrane but at different bilayer levels. While Lac705alpha interacts with the interfacial region inducing dehydration, Lac705beta peptide interacts with only the hydrophobic core. This paper presents the first experimental evidence that supports the hypothesis that Lac705alpha and Lac705beta peptides could form a transmembrane oligomer. From the obtained results, a mechanism of action of lactocin 705 on membrane systems is proposed. The component Lac705alpha could induce the dehydration of the bilayer interfacial region, and the Lac705beta peptide could insert in the hydrophobic region of the membrane where the peptide has adequate conditions to achieve the oligomerization.