title: Thyroid hormone is a MAPK-dependent growth factor for human myeloma cells acting via αvβ3 integrin.
abstract: 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.
authors.affiliation: Translational Hemato-Oncology Laboratory, Meir Medical Center, 59 Tchernichovsky St, Kfar-Saba 44281, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Cohen
authors.forename: Martin
authors.initials: M
authors.lastname: Ellis
authors.forename: Shafik
authors.initials: S
authors.lastname: Khoury
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
authors.forename: Aleck
authors.initials: A
authors.lastname: Hercbergs
authors.forename: Osnat
authors.initials: O
authors.lastname: Ashur-Fabian
mesh_terms: D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013974:Thyroxine / Q000378:metabolism / Q000494:pharmacology*; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D039302:Integrin alphaVbeta3; D014284:Triiodothyronine; D020928:Mitogen-Activated Protein Kinases; D013974:Thyroxine