Data from Thyroid Hormone Is a MAPK-Dependent Growth Factor for Human Myeloma Cells Acting via αvβ3 Integrin

Experimental and clinical observations suggest that thyroid hormone [l-thyroxine (T₄) and 3,5,3′-triiodo-l-thyronine (T₃)] can support cancer cell proliferation. T₃ and T₄ promote both tumor cell division and angiogenesis by activating mitogen-activated protein kinase (MAPK) via binding to a hormone receptor on the αvβ3 integrin, overexpressed on many cancer cells. We have studied the responsiveness of several MM cell lines to T₃ and T₄ and characterized hormonal effects on cell survival, proliferation, and MAPK activation. Overnight T₃ (1–100 nmol/L) and T₄ (100 nmol/L) incubation enhanced, up to 50% (P < 0.002), MM cell viability (WST-1 assay) and increased cell proliferation by 30% to 60% (P < 0.01). Short exposure (10 minutes) to T₃ and T₄ increased MAPK activity by 2.5- to 3.5-fold (P < 0.03). Pharmacologic MAPK inhibition blocked the proliferative action of T₃ and T₄. Antibodies to the integrin αvβ3 dimer and αv and β3 monomers (but not β1) inhibited MAPK activation and subsequent cell proliferation in response to thyroid hormone, indicating dependence upon this integrin. Moreover, tetraiodothyroacetic acid (tetrac), a non-agonist T₄ analogue previously shown to selectively block T₃/T₄ binding to αvβ3 receptor site, blocked induction of MAPK by the hormones in a dose-dependent manner. This demonstration of the role of thyroid hormones as growth factors for MM cells may offer novel therapeutic approaches. Mol Cancer Res; 9(10); 1385–94. ©2011 AACR.