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

Research Article

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

Faith B. Davis,1 Heng-Yuan Tang,2 Ai Shih,1 Travis Keating,2 Lawrence Lansing,1 Aleck Hercbergs,5 Robert A. Fenstermaker,6 Ahmed Mousa,3 Shaker A. Mousa,3 Paul J. Davis,1,2,4 and Hung-Yun Lin1,2

1Ordway Research Institute, Inc.; 2Research Service, Stratton Veterans Affairs Medical Center; 3Albany College of Pharmacy; 4Wadsworth Center, New York State Department of Health, Albany, New York; 5Department of Radiation Oncology, The Cleveland Clinic, Cleveland, Ohio; and 6Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York

Abstract RGD (arginine-glycine-aspartate) recognition site that is essential to the interactions of the integrin with its extracellular matrix Recent evidence suggests that the thyroid hormone L-thyroxine (ECM) protein ligands (2, 3). We have presented evidence that the (T4) stimulates growth of cancer cells via a plasma membrane thyroid hormone–binding site on integrin aVh3 is at or near the receptor on integrin AVB3.The contribution of this recently described receptor for thyroid hormone and receptor-based RGD recognition site and that an RGD peptide will displace stimulation of cellular mitogen-activated protein kinase thyroid hormone from integrin and will block the cellular actions [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2)] of the hormone (1). An interesting feature of this hormone activity, to enhancement of cell proliferation by thyroid receptor is that tetraiodothyroacetic acid, a hormone analogue hormone was quantitated functionally and by immunologic with reduced thyromimetic activity (4), competes with T4 at the means in three glioma cell lines exposed to T .At concen- receptor site (1). 4 Glioblastoma, the most common primary brain tumor in adults trations of 1 to 100 nmol/L, T4 caused proliferation of C6, F98, and GL261 cells, measured by accumulation of proliferating (5, 6), carries a poor prognosis despite a variety of therapeutic cell nuclear antigen (PCNA) and radiolabeled thymidine approaches. The astrocyte is the cell of origin in glioblastomas, and incorporation.This effect was inhibited by the T analogue, astrocytes have been shown previously to be a focus of thyroid 4 hormone action (7–9). Modulation of the state of actin (7, 10) and tetraiodothyroacetic acid, and by an AVB3 RGD recognition site peptide, both of which block T binding to integrin A B but interactions of astrocyte integrin with the ECM protein, laminin 4 V 3 (9), have been reported. By stimulation of growth factors, such as are not agonists.Activation of MAPK by T 4 was similarly inhibited by tetraiodothyroacetic acid and the RGD peptide. basic fibroblast growth factor (FGF), thyroid hormone may stimulate neuronal cell proliferation (11). Hercbergs et al. (12) The thyroid hormone 3,5,3¶-triiodo-L-thyronine (T3) and T4 were equipotent stimulators of PCNA accumulation in C6, F98, have reported in 2003 that glioblastoma patients rendered mildly and GL261 cells, but physiologic concentrations of T are hypothyroid by thioamide treatment exhibit significantly improved 3 duration of survival, raising the possibility that endogenous thyroid 50-fold lower than those of T4.In conclusion, our studies suggest that glioblastoma cells are thyroid hormone dependent hormone may be a growth factor for glioblastoma. and provide a molecular basis for recent clinical observations Other neoplasms may also be subject to the growth-promoting activity of thyroid hormone. Cristofanilli et al. (13) showed in that induction of mild hypothyroidism may improve duration of survival in glioblastoma patients.The present experiments 2005 that spontaneous clinical hypothyroidism may decrease the infer a novel cell membrane receptor-mediated basis for the aggressiveness of breast cancer and reduce the incidence of the growth-promoting activity of thyroid hormone in such tumors tumor. We have reported that the response of MCF-7 breast and suggest new therapeutic approaches to the treatment of cancer cells to treatment with a physiologic concentration of T4 is patients with glioblastoma. (Cancer Res 2006; 66(14): 7270-5) cell proliferation, measured by either the appearance of proliferating cell nuclear antigen (PCNA) or the cellular uptake of tritiated thymidine (14). This latter effect of T is reproduced Introduction 4 by exposure of cells to T4-agarose, an immobilized form of the We have described recently a specific cell surface receptor for hormone that cannot enter the cell (14), implicating a cell surface a h the thyroid hormone L-thyroxine (T4) on integrin V 3 that is receptor site in this trophic effect of thyroid hormone on breast linked to the activation of hormone of mitogen-activated protein cancer cells. kinase [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2)] With this evidence for a cell surface receptor site as the initial and, downstream of MAPK, to complex transcriptional events, step in the trophic effect of thyroid hormone on breast cancer such as angiogenesis (1). The integrins are structural plasma cells and the clinical evidence supporting a role for thyroid membrane proteins whose extracellular domains bind to matrix hormone in the growth of glioblastoma, we have examined the and other proteins and whose intracellular domains have been possibility that iodothyronines, acting at the cell surface, are a h shown by others to activate MAPK (2). Integrin V 3 contains an growth factors for a rat glioma (C6) cell line as well as other glial tumor models.

Requests for reprints: Faith B. Davis, Ordway Research Institute, Inc., 150 New Scotland Avenue, Albany, NY 12208. Phone: 518-641-6465; Fax: 518-641-6303; E-mail: Materials and Methods [email protected]. I2006 American Association for Cancer Research. Cell lines. The rat glioma cell line C6 was purchased from American doi:10.1158/0008-5472.CAN-05-4365 Type Culture Collection (Rockville, MD), whereas F98 and GL261 cells were

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1 hour. The supernatants were collected after subsequent centrifugation at 4jC and 13,000 rpm for 10 minutes. Immunoblotting. The techniques have been standardized in our laboratory (15–17). Nucleoproteins were separated on discontinuous SDS-PAGE and then transferred by electroblotting to nitrocellulose membranes (Millipore, Bedford, MA). After blocking with 5% milk in TBS containing 0.1% Tween 20, the membranes were incubated with various antibodies overnight. Secondary antibodies were either goat anti-rabbit IgG (1:1,000; DAKO) or rabbit anti-mouse IgG (1:1,000; DAKO), depending on the origin of the primary antibody. Immunoreactive proteins were detected by chemiluminescence, and blots were quantitated densitometrically. All experiments were carried out at least thrice with results normalized to a value of 1 in control samples. Thymidine incorporation. Aliquots of cells were each incubated with 1 ACi [3H]-thymidine (Amersham Bioscience, Piscataway, NJ), in a final concentration of 13 nmol/L and in a 24-well culture tray for 16 hours. Cells were then washed twice with cold PBS. TCA (5%) was added, and the plate was held at 4jC for 30 minutes. The precipitate was washed twice with cold ethanol; 2% SDS (1 mL) was then added to each well, and TCA-precipitable radioactivity was quantitated in a liquid scintillation counter.

Results Thyroid hormone causes glial cell proliferation. We have shown recently that T4 induces expression of PCNA in human breast cancer cells (14). A similar response to T4 was seen in three different glioma cell lines, as shown by representative studies seen in Fig. 1A. C6, F98, and GL261 cells were treated for 24 hours with T4, and a dose-response effect was evident with hormone concentrations from 1 to 100 nmol/L. In addition, radiolabeled thymidine incorporation studies were used to characterize this hormone effect. A concentration-dependent response to T4, comparable with that seen in PCNA expression studies, is seen

Figure 1. L-Thyroxine (T4) stimulates accumulation of PCNA and uptake of in a representative thymidine uptake study in C6 cells, with the A, radiolabeled thymidine in C6,F98,and GL261 glioma cells. T4 stimulated greatest effect seen at a physiologic hormone concentration of accumulation of PCNA in C6,F98,and GL261 cells at total hormone B concentrations of 1 to 100 nmol/L over a 24-hour period. This effect was T4 100 nmol/L (Fig. 1 ). concentration dependent. Representative of three experiments with each cell line. The GL261 cells showed some PCNA antigen in the absence of hormone, and hormone concentration-dependent PCNA was further increased by T4, as shown in the representative immunoblot and graph derived from results of three experiments. B, in combined results from three studies of radiolabeled thymidine incorporation,a similar dose-response effect of T 4 (1-100 nmol/L) is seen in C6 cells. available in the laboratory of author R.A.F. C6 cells were maintained in F12K medium supplemented with 10% fetal bovine serum (FBS). F98 and GL261 cells were maintained in DMEM supplemented with 10% FBS. All cell cultures were cultured in a 5% CO2/95% air incubator at 37jC. Before treatment, cells were exposed to 0.25% hormone-stripped FBS-containing medium for 2 days (14).

Reagents and antibodies. T4,T3, tetraiodothyroacetic acid, RGD peptide, and phorbol 12-myristate 13-acetate (PMA) were obtained from Sigma-Aldrich Corp. (St. Louis, MO). Polyclonal rabbit anti-phosphorylated MAPK (anti-pERK1/pERK2) was purchased from Cell Signaling (Beverly, MA), and monoclonal mouse anti-PCNA was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Goat anti-rabbit IgG and rabbit anti- mouse IgG were purchased from DAKO (Carpinteria, CA). Chemilumines- cence reagent (enhanced chemiluminescence) was from Amersham (Piscataway, NJ). PD98059, a MAPK kinase [MAPK/ERK kinase (MEK)] inhibitor, was purchased from Calbiochem (La Jolla, CA), and RGD peptide Figure 2. Pretreatment with RGD peptide or tetraiodothyroacetic acid was from Sigma-Aldrich. CGP41251, a protein kinase C (PKC) inhibitor, was before addition of T4 results in inhibition of the hormone effect on PCNA kindly provided by Ciba-Geigy (Basel, Switzerland). expression in C6 cells. Cells pretreated with RGD peptide (5-500 nmol/L) or Cell fractionation. Cell fractionation and preparation of nucleoproteins tetraiodothyroacetic acid (tetrac) (100 nmol/L) for 30 minutes showed inhibition of T4-stimulated cellular PCNA expression. The response to RGD peptide was dose were done as in previously reported methods (15). Nuclear extracts were dependent. Neither the peptide nor tetraiodothyroacetic acid alone significantly prepared by resuspension of the crude nuclei in high-salt buffer (hypotonic affected PCNA expression. Top, representative study; bottom, results of buffer with 420 mmol/L NaCl and 20% glycerol) at 4jC with rocking for three similar experiments. www.aacrjournals.org 7271 Cancer Res 2006; 66: (14). July 15, 2006

a h T4 stimulation of C6 cell proliferation requires hormone or absence of integrin V 3 RGD peptide (5-500 nmol/L). This interaction with its plasma membrane receptor, integrin AVB3. peptide has been shown to block interaction of protein ligands As indicated above, several nongenomic actions of T4, effects that with the integrin (2, 3), as well as the interaction of L-thyroxine do not require primary interaction of the hormone with the with the integrin (1). T4 caused nuclear accumulation of nuclear thyroid hormone receptor, TRh1, are initiated at a phosphorylated MAPK (pERK1/2) in C6 cell nuclei (Fig. 3A), plasma membrane receptor on integrin aVh3. Such actions can indicating kinase activation and consequent translocation to the be blocked with simultaneous administration of either the T4 nucleus. This thyroid hormone-induced MAPK activation was analogue tetrac (tetraiodothyroacetic acid) or an RGD peptide, inhibited by the RGD peptide in a peptide concentration- both of which inhibit hormone binding to the integrin receptor dependent manner (Fig. 3A). The RGD peptide, alone, did not (1). C6 cells were therefore incubated with T4 in the presence or activate MAPK. Tetraiodothyroacetic acid, which inhibits binding absence of these inhibitors (Fig. 2). Increasing concentrations of of T4 to the integrin receptor, did not cause MAPK activation but the RGD peptide (5-500 nmol/L) progressively inhibited the inhibited the activation of MAPK by T4 (Fig. 3B). Similar studies hormone effect on PCNA expression, shown in both representa- were conducted in F98 glioma cells and are seen in Fig. 3C. Again, tive immunoblot above and the graph below, which summarizes T4 stimulation of ERK1/2 phosphorylation and appearance of the results of three experiments. Tetraiodothyroacetic acid alone PCNA were both suppressed by tetraiodothyroacetic acid. These had no effect on PCNA expression but blocked the proliferative studies were also conducted in GL261 glioma cells, and Fig. 3D effect of T4 in C6 cells, consistent with inhibition of T4 binding to shows inhibition by tetraiodothyroacetic acid of both MAPK integrin aVh3 (1). activation and cell proliferation induced by T4. L-Thyroxine induces MAPK (ERK1/2) activation in glial cells, Treatment of C6 cells with T4 in the presence of the MEK an effect requiring conventional PKC activation and blocked (MAPK kinase) inhibitor, PD98059, produced an expected loss of by RGD peptide and tetraiodothyroacetic acid. On interaction hormone action on nuclear accumulation of phosphorylated with the plasma membrane integrin receptor, T4 stimulates the ERK1/2 (Fig. 4A). PD98059 in the absence of thyroid hormone MAPK pathway, resulting in phosphorylation and nuclear translo- had no effect on activation of MAPK. We have shown previously cation of ERK1/2 (1, 15). This effect may take place in the presence that activation of MAPK by T4 requires activity of a conventional (16–18) or absence (1, 15, 18) of the nuclear thyroid hormone PKC (cPKC; ref. 15). The contribution of cPKC to T4-induced receptor, TRh1, and is therefore independent of TRh1. Rat C6 MAPK activation was shown in C6 cells; such activation was glioma cells were treated with a physiologic total concentration of blocked by the cPKC inhibitor, CGP41251, in a dose-dependent T4 (100 nmol/L total or <0.1 nmol/L free T4; ref. 1), in the presence manner (Fig. 4A). Further, depletion of cellular PKC by

Figure 3. RGD peptide and tetraiodothyroacetic acid inhibit T4 stimulation of MAPK activation and cell proliferation in glioma cells. A, the RGD peptide alone did not significantly stimulate activation of MAPK in C6 cells. T4 (100 nmol/L) promoted activation of MAPK, as shown by nuclear accumulation of phosphorylated ERK1/2. This latter effect was progressively suppressed by increasing concentrations of the RGD peptide (5-500 nmol/L). Top, representative immunoblot; bottom, normalized results of three similar experiments. B, T4-stimulated MAPK activation in C6 cells was also suppressed by coincubation of T4 (100 nmol/L) with tetraiodothyroacetic acid (tetrac) (100 nmol/L),a finding that we have reported previously in other cell lines (15). Bottom, results of three similar experiments. C, in F98 cells,T 4-stimulated MAPK activation and enhanced PCNA accumulation were inhibited by the addition of tetraiodothyroacetic acid. Bottom, normalized results of three similar PCNA studies. D, in GL261 cells,MAPK activation and accumulation of PCNA,stimulated by T4,were both decreased by the addition of tetraiodothyroacetic acid to the hormone incubation. Top, representative immunoblots of three similar experiments; bottom, results of three PCNA experiments.

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concentrations of either PD98059 or CGP41251, indicating dependence of the effect on cPKC activation and stimulation of the MAPK activation pathway. L-T3 also stimulates glioma cell proliferation and thymidine incorporation. Parallel studies were conducted with T3, the traditional ligand of the nuclear thyroid hormone receptor, TRh1. This thyroid hormone also stimulated proliferation of C6, F98, and GL261 cells (Fig. 5A), although the concentrations needed for this effect were supraphysiologic, except with GL261 cells, which expressed PCNA without hormone treatment. We have reported a h that the affinity of V 3 for T3 is substantially lower than the affinity for T4 (1). C6 cell proliferation with T3 treatment was also measured by thymidine incorporation, and results again showed a concentration-dependent hormone response comparable with the results of PCNA studies (Fig. 5B).

Discussion We have shown recently that a binding site for thyroid hormone exists on the cell surface at an integrin (aVh3) that is linked to MAPK activity (1), angiogenesis (1), and cell migration (10). The existence of an initiation site for these so-called nongenomic actions of the hormone actions that do not primarily require

Figure 4. T4 stimulation of MAPK activation in C6 cells is dependent on cPKC activity. A, T4 treatment of C6 cells resulted in activation of MAPK (formation and nuclear translocation of pERK1/2). PD98059 (PD; 3-30 Amol/L) inhibited ERK1/2 phosphorylation,as expected. The cPKC inhibitor,CGP41251 (CGP; 10-100 nmol/L) also suppressed the T4 effect in a dose-dependent manner,as we have reported previously (15). Top, representative immunoblot; bottom, results of three similar experiments. B, MAPK activation in C6 cells was stimulated by T4,but this effect was blocked by PMA treatment (100 ng/mL for 24 hours). Short-term PMA treatment (30 minutes) did not affect hormone action (results not shown). Top, representative immunoblot; bottom, results of three experiments. C, C6 cell PCNA was measured in the presence or absence of T4 and/or PD98059 or CGP41251. Hormone-stimulated PCNA accumulation was progressively inhibited by increasing concentrations of either inhibitor,indicating dependence of the hormone effect on both cPKC and ERK1/2 activation pathways. Top, representative immunoblot of three experiments. pretreatment of cells with phorbol ester (PMA) for 24 hours eliminated the effect of hormone on MAPK activation (Fig. 4B). In contrast, short-term treatment of cells with PMA resulted in Figure 5. T3 stimulates accumulation of PCNA in glioma cells. A, PCNA activation of MAPK (pERK1/2) in the absence of T4, and addition accumulation was seen in C6, F98, and GL261 cells treated with 3,5,3¶-triiodo- of hormone caused no significant further increase in MAPK L-thyronine (T3),1 to 1,000nmol/L. In C6 and F98 cells,this occurred with z activation (Fig. 4B). The effects of MAPK and cPKC inhibition on T3 concentrations which are supraphysiologic ( 1 nmol/L). As also seen in C Figs. 1A and 3D,the GL261 cells expressed PCNA even in the absence of T4-induced accumulation of PCNA in C6 cells are seen in Fig. 4 . hormone. B, radiolabeled thymidine incorporation was measured in C6 cells The hormone effect was progressively inhibited by increasing treated with 0.1 to 1,000 nmol/L T3. www.aacrjournals.org 7273 Cancer Res 2006; 66: (14). July 15, 2006

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2006 American Association for Cancer Research. Cancer Research intranuclear binding of thyroid hormone to its nuclear receptor reproduced in Israel by a group with which Hercbergs is mediated by an integrin caused us to speculate that glioma cell associated (25). Thyroid hormone is known to cross the blood- growth in response to thyroid hormone might in fact occur via brain barrier (26, 27), and as noted above, glial cells are central a h integrin V 3. The observations reported in the present article nervous system targets of thyroid hormone action (10, 28). Glial implicate this integrin in promotion by thyroid hormone of cell cell migration and, by extension, glial tumor cell migration would growth of glioma cells. The location of the thyroid hormone– be facilitated by ambient levels of thyroid hormone that act to binding site is at or near the RGD recognition site on the integrin, maintain actin in the F-state (28) and that modulate astrocyte as shown elsewhere by the ability of RGD peptide to competitively integrin-ECM protein interactions (9). Fostering of angiogenesis by displace T4 from the integrin (1). We show here, via inhibition or thyroid hormone (1, 24) is an adjunctive factor that would also depletion of PKC upstream of MAPK or via inhibition of the MAPK serve to support tumor growth. (ERK1/2) pathway at MEK, that the integrin mediates the The present in vitro observations provide a cellular mechanism activation of this pathway and, downstream of MAPK, the action by which thyroid hormone can be a growth factor for glioma and of T4 on cell division, when the latter was measured by PCNA the rationale for the clinical observations that reducing ambient accumulation or [3H]-thymidine incorporation. RGD peptide and (i.e., physiologic) levels of thyroid hormone may improve tetraiodothyroacetic acid both blocked the cell growth-promoting duration of survival in glioblastoma patients. Because our activity of thyroid hormone, consistent with initiation of the in vitro observations indicate that the tumor cell growth-promoting thyroid hormone effect at the cell surface receptor for thyroid activity of thyroid hormone begins at the integrin receptor for the hormone that we have described (1). hormone; however, treatment strategies may exist that are Promotion of glioma cell proliferation (19, 20) and differentia- alternatives to induction of clinical hypothyroidism. For example, tion (21) by thyroid hormone in vitro has been described by several tetraiodothyroacetic acid may be used systemically to block laboratories. The hormone also affects myelin gene expression and endogenous thyroid hormone–binding to the integrin; tetraiodo- survival of developing oligodendrocytes (22). In addition, thyroid thyroacetic acid has low-grade thyromimetic activity, except for hormone conditions the relationship of glial cells with ECM competition with T4 and T3 at the cell surface receptor site. proteins, such as laminin (9, 23) and fibronectin (23). Differenti- Proprietary small molecules are also available in our laboratory ation that is caused by iodothyronines is p21 dependent (20), and that mimic the RGD peptide sequence, and we have shown that the cell-ECM relationship is, at least in part, a function of the such molecules can interfere with actions of thyroid hormone action of thyroid hormone on cellular release of FGF (11). The that are dependent on the integrin receptor site (29). Use of molecular basis for initiation of these actions of thyroid hormone either of these strategies would permit actions of endogenous has not been fully defined; however, we have reported previously thyroid hormone, specifically T3, on mitochondrial respiration to that iodothyronines can induce FGF2 secretion in endothelial cells persist, as well as genomic actions of the hormone that are by a mechanism that is MAPK (ERK1/2) dependent (24). We have mediated directly by liganding to the nuclear thyroid hormone observed a secondary increase in MAPK activation at 24 hours in receptor. C6 cells exposed to thyroid hormone (results not shown), which may in fact reflect increased FGF2 secretion, as we have proposed in the proangiogenic action of thyroid hormone (24). Acknowledgments Clinical observations by Hercbergs et al. (12) suggest that the Received 12/7/2005; revised 4/2/2006; accepted 4/26/2006. growth of glioblastoma multiforme is thyroid hormone dependent. Grant support: Office of Research Development, Medical Research Service, and Department of Veterans Affairs (P.J. Davis and H-Y. Lin); Charitable Leadership These authors induced mild chemical hypothyroidism by inter- Foundation; Candace King Weir Foundation; and Beltrone Foundation. fering with thyroid hormonogenesis through administration of The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance propylthiouracil and obtained a 3-fold increase in duration of with 18 U.S.C. Section 1734 solely to indicate this fact. survival of patients. This experience in the United States has been We thank Douglas Hammond and Jack Qian for excellent technical assistance.

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Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2006 American Association for Cancer Research. Acting via a Cell Surface Receptor, Thyroid Hormone Is a Growth Factor for Glioma Cells

Faith B. Davis, Heng-Yuan Tang, Ai Shih, et al.

Cancer Res 2006;66:7270-7275.

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