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 alpha(V)beta(3). 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 T-4. At concentrations of 1 to 100 nmol/L, T-4 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 alpha(V)beta(3) RGD recognition site peptide, both of which block T-4 binding to integrin 003 but are not agonists. Activation of MAPK by T-4 was similarly inhibited by tetraiodothyroacetic acid and the RGD peptide. The thyroid hormone 3,5,3'-triiodo-L-thyronine (T-3) and T-4 were equipotent stimulators of PCNA accumulation in C6, F98, and GL261 cells, but physiologic concentrations of T-3 are 50-fold lower than those of T-4. 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.