Relevance of the thyroid hormones-αvβ3 pathway in primary myeloma bone marrow cells and to bortezomib action

Thyroid hormones (T-3 and T-4) induce proliferation in multiple myeloma (MM) cell lines via the alpha v beta 3 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 T-3 (13%, p < 0.002) and more potently by 100 nM T-4 (21-45%, p < 0.0002) and a quick (1 h) and long-lasting (24 h) pERK activation, which was inhibited in the presence of beta 3 but not beta 1 blocking antibodies. Involvement of the integrin was further shown by two disintegrins, Arg-Gly-Asp (RGD) and echistatin peptides, which occluded the effects of T-3/T-4 on viability, proliferating cell nuclear antigen (PCNA) (proliferation marker) and apoptotic gene expression. Lastly, T-3/T-4 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.