Acting via a Cell Surface Receptor, Thyroid Hormone Is a Growth Factor for Glioma Cells

Abstract

Recent evidence suggests that the thyroid hormone L-thyroxine (T 4 ) stimulates growth of cancer cells via a plasma membrane receptor on integrin A V B 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 A V B 3 RGD recognition site peptide, both of which block T 4 binding to integrin A V B 3 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. (Cancer Res 2006; 66(14): 7270-5)

l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

“…3B). As anticipated from our previous studies (3,7,8), T 4 -stimulated cell proliferation and ERK1/2 activation were completely blocked by tetrac (Fig. 3B).…”

“…An additional example of nongenomic/genomic cross talk is thyroid hormone-stimulated cell proliferation. The latter is ERK1/2-dependent, requires new blood vessel formation (7), and has been described in human breast cancer cells (39) and glioma cells (8).…”

“…We have previously shown that T 4 , via binding to cell membrane integrin ␣ v ␤ 3 , activates ERK1/2 and that this activation can be blocked by an RGD peptide (3,8).…”

“…Further studies were carried out with the thyroid hormone analog tetrac, which, like the RGD peptide, also inhibits thyroid hormone binding to integrin ␣ v ␤ 3 (3,8). Tetrac alone did not induce ERK1/2 activation, cell proliferation.…”

“…Fractionation in a microfuge and preparation of nucleoproteins was by our previously reported methods (8,27,28). Nuclear extracts were prepared by resuspension of the crude nuclei in high-salt buffer (hypotonic buffer containing 420 mM NaCl and 20% glycerol) at 4°C with rocking for 1 h. The supernatants were collected after subsequent centrifugation at 4°C and 13,000 revolutions/min for 10 min.…”