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 (T(4)) and 3,5,3'-triiodo-l-thyronine (T(3))] can support cancer cell proliferation. T(3) and T(4) 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 T(3) and T(4) and characterized hormonal effects on cell survival, proliferation, and MAPK activation. Overnight T(3) (1-100 nmol/L) and T(4) (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 T(3) and T(4) increased MAPK activity by 2.5- to 3.5-fold (P < 0.03). Pharmacologic MAPK inhibition blocked the proliferative action of T(3) and T(4). 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 T(4) analogue previously shown to selectively block T(3)/T(4) 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.