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Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via ?v?3 integrin in myeloma cells.

ABSTRACT: 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 ?v?3 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 ?v?3 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 ?v?3 clustering. In addition, the hormones induced MMP-9 expression and activation via ?v?3 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 ?v?3 of myeloma cell adhesion and MMP-9 production may play a role in myeloma migration and progression.

SUBMITTER: Cohen K

PROVIDER: S-EPMC4171632 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Project description:Adhesive and migratory behavior can be cell type, integrin, and substrate dependent. We have compared integrin and substrate differences using three integrin receptors: ?5?1, ?6?1, and ?L?2 expressed in a common cell type, CHO.B2 cells, which lack integrin ? subunits, as well as in different cell types that express one or more of these integrins. We find that CHO.B2 cells expressing either ?6?1 or ?L?2 integrins migrate and protrude faster and are more directionally persistent on laminin or ICAM-1, respectively, than CHO.B2 cells expressing ?5?1 on fibronectin. Despite rapid adhesion maturation and the presence of large adhesions in both the ?6?1- and ?L?2-expressing cells, they display robust tyrosine phosphorylation. In addition, whereas myosin II regulates adhesion maturation and turnover, protrusion rates, and polarity in cells migrating on fibronectin, surprisingly, it does not have comparable effects in cells expressing ?6?1 or ?L?2. This apparent difference in the integration of myosin II activity, adhesion, and migration arises from alterations in the ligand-integrin-actin linkage (molecular clutch). The elongated adhesions in the protrusions of the ?6?1-expressing cells on laminin or the ?L?2-expressing cells on ICAM-1 display a novel, rapid retrograde flux of integrin; this was largely absent in the large adhesions in protrusions of ?5?1-expressing cells on fibronectin. Furthermore, the force these adhesions exert on the substrate in protrusive regions is reduced compared to similar regions in ?5-expressing cells, and the adhesion strength is reduced. This suggests that intracellular forces are not efficiently transferred from actomyosin to the substratum due to altered adhesion strength, that is, avidity, affinity, or the ligand-integrin-actin interaction. Finally, we show that the migration of fast migrating leukocytes on fibronectin or ICAM-1 is also largely independent of myosin II; however, their adhesions are small and do not show retrograde fluxing suggesting other intrinsic factors determine their migration differences.

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Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via ?v?3 integrin in myeloma cells.

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