Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via αvβ3 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 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.

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

“…The concentrations selected for T3 (1 nM) and T4 (100 nM) are slightly supraphysiological and physiological, respectively, as previously reported by our group in other experimental cancer models. [28][29][30] By using fluorescently dye-tagged T3 and T4, the membrane binding of the two hormones to OVCAR-3 cells (Figure 1b binding was scarcely detectable. Furthermore, an overnight incubation of OVCAR-3 cells with T3 or T4, induced clustering and abundance of the integrin on the cell surface by 2.5-fold and fourfold (quantified using NIH ImageJ software), respectively ( Figure 1c).…”

“…62 This trafficking event was also shown to be ERK-dependent. 62 Given that the activation of ERK has been closely correlated with the thyroid hormonal action in cancer cells, 17,18,26,[28][29][30][63][64][65][66][67][68][69] together with the central role of MAPK in ovarian cancer, 70 led us to explore this pathway in our experimental system. Results in ovarian cancer cells similarly indicate activation of ERK by the hormones.…”

“…These results are consistent with our recently reported work in which a reduction of host circulating T4 levels postponed clinical progression of a variety of aggressive solid tumors, including two cases of ovarian cancer. 90 Using pharmacological inhibitors of the hormonal receptor site on the αvβ3 integrin, which were developed by our group, we were able to abrogate an array of signaling events in various cancer cells in vitro 29,30,91,92 and extend survival in vivo. 93,94 Additional novel agents are under investigation (unpublished data).…”

Thyroid hormones and tetrac: new regulators of tumour stroma formation via integrin αvβ3

“…Balzan et al (2013) reported similar effects on microvascular endothelial cells in a wound-healing assay with increased migration after T 3 or T 4 stimulation that was abolished by treatment with tetrac. Studies on multiple myeloma cells and bone marrow aspirates from multiple myeloma patients by Cohen et al (2014) illustrate thyroid hormone-dependent, avb3-mediated regulation of cell migration. Furthermore, there is growing evidence that thyroid hormones increase the motility of avb3-expressing immune cells, and, possibly by similar mechanisms, nerve cell migration (De Vito et al 2012).…”

Extracellular vesicle cross-talk in the bone marrow microenvironment: implications in multiple myeloma

“…BMSCs play crucial roles in MM progression and induction of drug resistance through cell-cell contact and secretion of cytokines [1, 145, 146]. MM cells adhere to BMSCs, stimulating the latter to secrete more soluble factors which mediate MM cell growth, survival, migration, drug resistance, and BM angiogenesis [145, 147–151].…”