Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells

Recent evidence suggests that the thyroid hormone L-thyroxine (T ₄) stimulates growth of cancer cells via a plasma membrane receptor on integrin α_Vβ₃. The contribution of this recently described receptor for thyroid hormone and receptor-based stimulation of cellular mitogen-activated protein kinase [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2)] activity, to enhancement of cell proliferation by thyroid hormone was quantitated functionally and by immunologic means in three glioma cell lines exposed to T₄. At concentrations of 1 to 100 nmol/L, T₄ caused proliferation of C6, F98, and GL261 cells, measured by accumulation of proliferating cell nuclear antigen (PCNA) and radiolabeled thymidine incorporation. This effect was inhibited by the T ₄ analogue, tetraiodothyroacetic acid, and by an α _Vβ₃ RGD recognition site peptide, both of which block T₄ binding to integrin α_Vβ₃ but are not agonists. Activation of MAPK by T₄ was similarly inhibited by tetraiodothyroacetic acid and the RGD peptide. The thyroid hormone 3,5,3′-triiodo-L-thyronine (T₃) and T₄ were equipotent stimulators of PCNA accumulation in C6, F98, and GL261 cells, but physiologic concentrations of T₃ are 50-fold lower than those of T₄. In conclusion, our studies suggest that glioblastoma cells are thyroid hormone dependent and provide a molecular basis for recent clinical observations that induction of mild hypothyroidism may improve duration of survival in glioblastoma patients. The present experiments infer a novel cell membrane receptor-mediated basis for the growth-promoting activity of thyroid hormone in such tumors and suggest new therapeutic approaches to the treatment of patients with glioblastoma.