Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via αvβ3 integrin in myeloma cells
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Keren Cohen1,2,3, Nir Flint1,3, Shachar Shalev1,3, Daniel Erez1,3, Tal Baharal1,3, Paul J. Davis4, Aleck Hercbergs5, Martin Ellis1,3 and Osnat Ashur-Fabian1,2,3
1 Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
2 Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel
3 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
4 Department of Medicine, Albany Medical College, Albany, NY, USA
5 Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA
Osnat Ashur-Fabian , email:
Keywords: Integrin, myeloma, thyroid hormone, MMP-9, adhesion
Received: May 26, 2014 Accepted: July 11, 2014 Published: July 13, 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 αvβ3 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 αvβ3 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 αvβ3 clustering. In addition, the hormones induced MMP-9 expression and activation via αvβ3 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 αvβ3 of myeloma cell adhesion and MMP-9 production may play a role in myeloma migration and progression.
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