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Cohen K.,The Hematology Institute and Blood Bank | Cohen K.,Tel Aviv University | Ellis M.,The Hematology Institute and Blood Bank | Ellis M.,Tel Aviv University | And 7 more authors.
Leukemia and Lymphoma | Year: 2015

Abstract Thyroid hormones (T3 and T4) induce proliferation in multiple myeloma (MM) cell lines via the αvβ3 integrin-mitogen-activated protein kinase (MAPK) pathway. We further show in primary MM bone marrow (BM) samples (n = 9) induction of cell viability by 1 nM T3 (13%, p < 0.002) and more potently by 100 nM T4 (21-45%, p < 0.0002) and a quick (1 h) and long-lasting (24 h) pERK activation, which was inhibited in the presence of β3 but not β1 blocking antibodies. Involvement of the integrin was further shown by two disintegrins, Arg-Gly-Asp (RGD) and echistatin peptides, which occluded the effects of T3/T4 on viability, proliferating cell nuclear antigen (PCNA) (proliferation marker) and apoptotic gene expression. Lastly, T3/T4 significantly opposed bortezomib (25 nM) cytotoxicy, as confirmed by several methods. In summary, our results imply that endogenous thyroid hormones in myeloma are factors that may support cell growth, with relevance to bortezomib action. © 2014 Informa UK, Ltd.

Cohen K.,The Hematology Institute and Blood Bank | Cohen K.,Tel Aviv University | Flint N.,The Hematology Institute and Blood Bank | Flint N.,Tel Aviv University | And 12 more authors.
Oncotarget | Year: 2014

Thyroid hormone (3,5,3'-triiodothyronine, T3; L-thyroxine, T4) enhances cancer cell proliferation, invasion and angiogenesis via a discrete receptor located near the RGD recognition site on avß3 integrin. Tetraiodothyroacetic acid (tetrac) and its nanoparticulate formulation interfere with binding of T3/T4 to the integrin. This integrin is overexpressed in multiple myeloma (MM) and other cancers. MM cells interact with avß3 integrin to support growth and invasion. Matrix metalloproteinases (MMPs) are a family of enzymes active in tissue remodeling and cancer. The association between integrins and MMPs secretion and action is well established. In the current study, we examined the effects of thyroid hormone on myeloma cell adhesion, migration and MMP activity. We show that T3 and T4 increased myeloma adhesion to fibronectin and induced avß3 clustering. In addition, the hormones induced MMP-9 expression and activation via avß3 and MAPK induction. Bortezomib, a standard myeloma treatment, caused a decrease in activity/quantity of MMPs and thyroid hormone opposed this effect. RGD peptide and tetrac impaired the production of MMP-9 in cell lines and in primary BM cells from myeloma patients. In conclusion, thyroid hormone-dependent regulation via avß3 of myeloma cell adhesion and MMP-9 production may play a role in myeloma migration and progression.

Pereg D.,Meir Medical Center | Pereg D.,Tel Aviv University | Cohen K.,Tel Aviv University | Cohen K.,The Hematology Institute and Blood Bank | And 9 more authors.
Journal of Atherosclerosis and Thrombosis | Year: 2015

Aim: The circulating RNA levels are predictive markers in several diseases. We determined the levels of circulating p53-related genes in patients with acute ST-segment elevation myocardial infarction (STEMI), indicating major heart muscle damage. Methods: Plasma RNA was extracted from the patients (n=45) upon their arrival to the hospital (STEMI 0h) and at four hours post-catheterization (STEMI 4h) as well as from controls (n= 34). Results: Of 18 circulating p53-related genes, nine genes were detectable. A significantly lower incidence of circulating p21 (p<0.0001), Notch1 (p=0.042) and BTG2 (p<0.0001) was observed in the STEMI 0h samples in comparison to the STEMI 4h and control samples. Lower expression levels (2.1-fold) of circulating BNIP3L (p=0.011), p21 (3.4-fold, p=0.005) and BTG2 (6.3-fold, p=0.0001) were observed in the STEMI 0h samples in comparison to the STEMI 4h samples, with a 7.4-fold lower BTG2 expression (p<0.001) and 2.6-fold lower p21 expression (p=0.034) compared to the control samples. Moreover, the BNIP3L expression (borderline significance, p=0.0655) predicted the level of peak troponin, a marker of myocardial infarction. In addition, the BNIP3L levels on admission (p= 0.0025), at post-catheterization (p=0.020) and the change between the groups (p=0.0079) were inversely associated with troponin. The BNIP3L (p=0.0139) and p21 levels (p=0.0447) were also associated with a longer time to catheterization. Conclusions: Our results suggest that circulating downstream targets of p53 are inhibited during severe AMI and subsequently re-expressed after catheterization, uncovering possible novel death-orsurvival decisions regarding the fate of p53 in the heart and the potential use of its target genes as prognostic biomarkers for oxygenation normalization. © 2015, Japan Atherosclerosis Society. All rights reserved.

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