title: Relevance of the thyroid hormones-αvβ3 pathway in primary myeloma bone marrow cells and to bortezomib action.
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.
authors: Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center , Kfar-Saba , Israel.
authors: Keren
authors: K
authors: Cohen
authors: Martin
authors: M
authors: Ellis
authors: Elena
authors: E
authors: Shinderman
authors: Shafik
authors: S
authors: Khoury
authors: Paul J
authors: PJ
authors: Davis
authors: Aleck
authors: A
authors: Hercbergs
authors: Osnat
authors: O
authors: Ashur-Fabian
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D000069286:Bortezomib / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005434:Flow Cytometry; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013974:Thyroxine / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D039302:Integrin alphaVbeta3; D018809:Proliferating Cell Nuclear Antigen; D014284:Triiodothyronine; D000069286:Bortezomib; D020928:Mitogen-Activated Protein Kinases; D013974:Thyroxine
keywords: integrin; myeloma; thyroid hormone; αvβ3