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Cell, Tumor, and Stem Cell Biology |
1 Department of Otolaryngology, University of Pittsburgh Medical Center; 2 Department of Pharmacology, University of Pittsburgh Cancer Institute; 3 Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania; and 4 Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
Requests for reprints: Jennifer Rubin Grandis, Department of Otolaryngology, University of Pittsburgh Medical Center, 203 Lothrop Street, Suite 500, Pittsburgh, PA 15213. Phone: 412-647-5250; Fax: 412-647-0108; E-mail: jgrandis{at}pitt.edu.
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Abstract |
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(TGF-). Inhibition of tumor necrosis factor-–converting enzyme abrogated BK- or PGE2-mediated activation of EGFR signaling. Both PGE2 and BK stimulated head and neck squamous cell carcinoma (HNSCC) invasion via EGFR. Treatment of HNSCC cells with the BK antagonist CU201 resulted in growth inhibition. The combination of CU201 with the EGFR small-molecule inhibitor erlotinib resulted in additive inhibitory effects on HNSCC cell growth in vitro. Inhibition of the PGE2 synthesis pathway with sulindac induced HNSCC cytotoxicity at high doses (EC50, 620 µmol/L). However, combined inhibition of both EGFR with the tyrosine kinase inhibitor erlotinib and GPCR with sulindac at low doses of 6 and 310 µmol/L, respectively, resulted in synergistic killing of HNSCC tumor cells. Combined blockade of both EGFR and GPCRs may be a rational strategy to treat cancers, including HNSCC that shows cross-talk between GPCR and EGFR signaling pathways. (Cancer Res 2006; 66(24): 11831-9) |
Introduction |
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G protein–coupled receptors (GPCR) are ubiquitously expressed in epithelial cells. Several GPCR ligands have been shown to activate the EGFR pathway contributing to HNSCC carcinogenesis. We previously reported that stimulation of the gastrin-releasing peptide (GRP) receptor activates EGFR and modulates HNSCC growth and invasion (4). In addition, EGFR activation in response to GPCR ligands, including lysophosphatidic acid (LPA) and thrombin, has also been reported in HNSCC cells (5). We and others have previously shown that GPCR ligand stimulation results in increased autocrine secretion of EGFR ligands, including transforming growth factor- (TGF-) and amphiregulin (AR; refs. 4, 6). GPCR ligands prostaglandin E2 (PGE2) and bradykinin (BK) are inflammatory molecules that have been previously reported to contribute to the proliferation of colon and breast cancer cells, respectively (7, 8). PGE2 has been reported to activate EGFR in tumors, including colon cancer, by activating other molecules, including Src and matrix metalloproteinases (MMP; refs. 6, 9). BK also has been reported to stimulate proliferation in breast cancer cells via EGFR (10). Combined inhibition of EGFR and GPCR may lead to enhanced antitumor effects compared with single agents targeting EGFR alone.
Several studies have shown that decreased PGE2 synthesis using cyclooxygenase (COX)-2 inhibitors results in growth inhibition of cancers, including HNSCC (11, 12). Inhibition of BK with the BK receptor antagonist CU201 has been previously reported to inhibit the growth of lung cancer cells (13). The effects of BK and PGE2 on EGFR signaling and the antitumor efficacy of combined EGFR and BK receptor inhibition have not been investigated in HNSCC cells. The goal of the present study was to determine the role of the GPCR ligands PGE2 and BK in mediating HNSCC growth and invasion via EGFR-dependent and EGFR-independent pathways. The effects of PGE2 and BK stimulation on EGFR and downstream signaling, growth, and invasion were investigated. Finally, we examined the antitumor efficacy of combined targeting of EGFR and GPCR as a potential treatment regimen for HNSCC.
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Materials and Methods |
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Reagents. EGFR-specific tyrosine kinase inhibitors AG1478 and AG9 were obtained from Calbiochem-Novabiochem Corp. (San Diego, CA). Erlotinib and gefitinib were obtained from OSI Pharmaceuticals (Melville, NY) and AstraZeneca Pharmaceuticals (Wilmington, DE), respectively. Anti-EGFR antibody C225 was obtained from Imclone Systems, Inc. (New York, NY). The small-molecule c-Src inhibitor PD0180970 was obtained from Pfizer, Inc. (New York, NY). Human PGE2 and BK were obtained from Sigma-Aldrich Corp. (St. Louis, MO). Recombinant human EGF was obtained from Oncogene Research Products (Boston, MA). The antibody used to coimmunoprecipitate EGFR was obtained from Upstate Biotechnology (Lake Placid, NY). For immunoblotting, anti-EGFR antibody from Transduction Laboratories (Lexington, KY) was used. Phosphorylation of EGFR was detected by coimmunoprecipitation for EGFR followed by immunoblotting using phosphotyrosine antibody PY99 from Santa Cruz Biotechnology (Santa Cruz, CA). Antibodies against p44/42 mitogen-activated protein kinase (MAPK) and phosphorylated p4/42 MAPK were from Cell Signaling Technology, Inc. (Danvers, MA). Neutralizing antibodies to TGF- and heparin-binding EGF (HB-EGF) were obtained from Oncogene Research Products. Neutralizing antibody to AR was obtained from R&D Systems (Minneapolis, MN). HEMA3 cell staining kit was purchased from Fisher Scientific (Hampton, NH). The BK antagonist CU201 was synthesized as reported previously (13). Sulindac was obtained from Sigma-Aldrich. Tumor necrosis factor-–converting enzyme (TACE) small interfering RNA (siRNA) based on previously published sequences was obtained from Dharmacon International (Lafayette, CO; ref. 5). TGF- ELISA kit was obtained from Oncogene Research Products.
Cell treatments. HNSCC cells and EGFR KO or EGFR WT fibroblasts (2 x 104/mL) were plated in 10 cm2 plates. For mechanistic studies, cells were serum starved for 72 hours. During serum starvation, the medium was changed every 24 hours. For the experiments with inhibitors, cells were pretreated with AG9 or AG1478 (250 nmol/L), C225 (6 µg/mL), TGF- (7 µg/mL), HB-EGF (50 µg/mL), AR (15 µg/mL), or PD0180970 (500 nmol/L) for 2 hours. For TACE down-modulation, previously described TACE siRNA duplexes were used (5). Briefly, HNSCC cells (2 x 105) were transfected with TACE siRNA in the presence of LipofectAMINE 2000 (Invitrogen, Inc., Carlsbad, CA) and serum starved for 48 hours after transfection. Following treatments with inhibitors, HNSCC cells were stimulated with EGF (10 ng/mL), PGE2 (10 nmol/L), or BK (10 nmol/L) for 5 minutes to examine phosphorylation of EGFR and for 10 minutes to examine phosphorylation of MAPK. Cells were lysed as described previously (4). For in vitro proliferation studies, cells were serum starved for 24 hours followed by treatment with either PGE2 or BK (10 nmol/L) for 2 days. Cells were counted using vital dye exclusion.
In vitro invasion and cytotoxicity assays. In vitro invasion assays were carried out in growth factor–reduced Matrigel-coated Transwell chambers (BD Biosciences, San Jose, CA). Briefly, HNSCC cells 1483 (5,000 per well) were plated in the Transwell chamber in the presence of 2.5% serum, 10 nmol/L PGE2, or 10 nmol/L BK in the presence or absence of erlotinib (6 µmol/L). Cells were incubated at 37°C with 5% CO2 for 24 hours. Cells that invaded the Transwell chamber were fixed and stained using the HEMA3 staining solutions according to the manufacturers' instructions. The number of cells that invaded the Matrigel was determined under x200 magnification.
For in vitro cytotoxicity assays, 1483 cells were treated 24 hours after plating with EGFR tyrosine kinase inhibitor gefitinib (3 µmol/L) and/or BK antagonist CU201 (4 µmol/L) or a combination of erlotinib (6 µmol/L) and/or sulindac (310 µmol/L) at varying concentrations for 72 hours followed by cell counting determinations using vital dye exclusion.
Immunoblotting. Cell lysates were clarified by centrifugation at 14,000 rpm for 5 minutes followed by protein estimation. Protein (30 µg) was resolved on an 8% SDS-PAGE gel and immunoblotted for phosphorylated MAPK followed by MAPK (Cell Signaling Technology, Beverly, MA). Immunoprecipitation for EGFR was carried out with anti-EGFR antibody obtained from Upstate Biotechnology followed by immunoblotting for phosphotyrosine (PY99) and total EGFR (Transduction Laboratories). The same membrane was stripped and probed for EGFR to show equal loading (Transduction Laboratories). Autoradiographs were scanned and subjected to densitometry analyses using DigiDoc 1000 digital imaging system (Alpha Innotech, San Leandro, CA). For the phosphorylated and total p42/44 MAPK blots, the cumulative intensities of both the p42 as well as the p44 bands were estimated.
Statistical analysis. Statistical determinations were done using the StatXact (version 6) software (Cytel Software Corp., Cambridge, MA). For two-way comparisons for independent samples, the exact Wilcoxon test was used to compare two groups. For comparison of multiple independent samples, the Kruskal-Wallis test for equality of the three groups was used.
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Results |
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EGFR is activated by several ligands, including TGF-, HB-EGF, and AR. Several reports have shown that stimulation of HNSCC cells with GPCR ligands increases autocrine release of EGFR ligands in the supernatant (4, 17). EGFR ligands bind to the extracellular domain of EGFR, triggering signaling cascades downstream of EGFR, including MAPK (4). To elucidate the mechanism whereby GPCR ligands PGE2 and BK activate EGFR, HNSCC cells were pretreated with an EGFR-specific antibody (C225) that binds the extracellular ligand-binding domain of EGFR, preventing ligand binding. Cells were subsequently stimulated with either PGE2 or BK (10 nmol/L for 10 minutes). Although GPCR-mediated MAPK phosphorylation was partially abrogated on EGFR extracellular domain inhibition, the attenuation in phosphorylation was not significant (P = 0.42; Fig. 2C). This indicates that MAPK may be phosphorylated by EGFR-dependent as well as EGFR-independent mechanisms in HNSCC.
TGF-, but not HB-EGF or AR, is released by PGE2 or BK stimulation. We and others have previously shown that GPCR ligand stimulation of HNSCC cells facilitates cleavage of membrane-bound EGFR proligands TGF-, AR, and/or HB-EGF depending on the specific GPCR ligand used (4, 18). Neutralizing antibodies to TGF-, but not HB-EGF or AR, blocked PGE2- and BK-induced MAPK phosphorylation in HNSCC cells (P = 0.05 on comparing PGE2- or BK-stimulated levels of MAPK phosphorylation with those in the presence of TGF- neutralizing antibody; Fig. 3A–C
). Release of mature ligand increases phosphorylation of EGFR, triggering signaling events downstream of EGFR. These results suggest that, in HNSCC cells, the specific EGFR ligand activated depends on the precise GPCR stimulus.
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levels by ELISA. TACE down-modulation reduced levels of TGF- released into the supernatant on BK stimulation (P = 0.05; Fig. 4C). These results show that TACE contributes to the cleavage of TGF- proligand on BK stimulation. PGE2 and BK stimulate HNSCC cell proliferation and invasion via EGFR. PGE2 and BK are inflammatory factors that have been previously reported to stimulate growth of colon or breast cancer cells, respectively (7, 10). The effect of PGE2 or BK on the growth of head and neck cancer cells has not been described previously. To determine the effects of PGE2 and BK on HNSCC proliferation, 1483 cells were stimulated with either 0.1 or 10 nmol/L of either PGE2 or BK for 3 days. Cell counts revealed that both ligands stimulated HNSCC cell proliferation compared with vehicle control–treated cells in a dose-dependent manner (P < 0.05; Fig. 5A ).
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In addition to being mitogenic, both PGE2 and BK have been previously reported to stimulate invasion of cancer cells (9, 22). The role of PGE2 or BK in HNSCC invasion has not been reported. To determine whether PGE2 or BK stimulates invasion via EGFR, HNSCC cells were plated in Matrigel-coated invasion chambers with 10 nmol/L of PGE2 or BK. Additional wells with GPCR ligands were treated with the EGFR-specific inhibitor erlotinib (6 µmol/L). Cells were allowed to invade toward serum-containing medium, which served as a chemoattractant over 24 hours. Both PGE2 and BK induced invasion of HNSCC cells, an effect that was abrogated in the presence of EGFR inhibition (P < 0.05; Fig. 5C). This indicates that both PGE2 and BK mediate invasion via an EGFR-dependent mechanism.
Combined inhibition of EGFR and BK or PGE2 improves growth inhibition in HNSCC. It has been suggested that targeting the EGFR axis at multiple levels may improve the antitumor effects of molecular targeted therapies (23). Our findings suggest that PGE2 and BK modulate HNSCC invasion primarily via EGFR. We postulated that combined targeting of both receptors may augment the antitumor effects of EGFR blockade. HNSCC cells were treated with increasing concentrations of the BK antagonist CU201 (0–16 µmol/L) for 72 hours. The EC50 obtained on CU201 treatment was found to be 8 µmol/L (Fig. 6A ). This dose is comparable with that reported previously in lung cancer cells (13). Next, HNSCC cells were treated with gefitinib (3 µmol/L) in combination with CU201 (4 µmol/L) for 72 hours. Additive growth-inhibiting effects were observed on combined inhibition of both receptors (Fig. 6B). Similar results were obtained on combining CU201 with erlotinib, another EGFR-specific small-molecule inhibitor (data not shown). Because PGE2 also had a growth-stimulatory effect, we examined the efficacy of combined inhibition of PGE2 and EGFR in HNSCC using the COX inhibitor sulindac. We elected to use the nonselective COX inhibitor sulindac rather than a COX-2 inhibitor, such as celecoxib, due to the recent cardiac toxicities of COX-2 inhibition and, therefore, the limited application for clinical development (24). HNSCC cells (1483) were exposed to increasing doses of sulindac for 72 hours. HNSCC cells were sensitive to sulindac treatment with a EC50 dose of 620 µmol/L (Fig. 6C). Combining sulindac (310 µmol/L) and EGFR inhibitor erlotinib (6 µmol/L) for 72 hours resulted in synergistic growth inhibition in HNSCC cells (Fig. 6D).
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Discussion |
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GPCRs are involved in many biological functions, including inflammation, cell growth, chemotaxis, and oncogenesis. Several recent reports provide evidence linking inflammation and tumor promotion. Inflammatory molecules, such as PGE2 and BK, in the tumor microenvironment have been reported to bind GPCRs and induce mitogenesis and invasion in several cancers, including breast and colon (9, 10). GPCR-mediated transactivation of EGFR has been shown to result in downstream activation of p44/42 MAPK (17, 30). Depending on the cell type and the GPCR ligand, MAPK may be activated via EGFR-dependent and/or EGFR-independent mechanisms. BK was reported to mediate MAPK activation independent of EGFR via a phosphatidylinositol 3-kinase and protein kinase C (PKC) pathway in vulvar carcinoma A431 cells (31). EGFR-dependent MAPK activation has been reported to result from GPCR-mediated EGFR activation via a variety of both intracellular and extracellular mechanisms (17).
Proposed intracellular mechanisms of EGFR transactivation by GPCRs have included roles for the serine/threonine kinase PKC (32), the nonreceptor tyrosine kinases of the Src family (27), and increased intracellular calcium levels (33). The mechanism of activation of EGFR by GPCRs seems to depend on the cell type and the specific GPCR ligand involved. Originally thought to be exclusively regulated by intracellular pathways, our results corroborate evidence suggesting that the EGFR extracellular domain is involved in GPCR-EGFR cross-talk (28). Several EGFR ligands have been detected in HNSCC cells, including betacellulin and AR, in addition to EGF, TGF-, and HB-EGF (34). We have previously shown that down-modulation of TGF- results in inhibition of HNSCC growth, indicating that TGF- is primarily involved in autocrine activation of EGFR in head and neck cells (35). Further, enhanced TGF- levels in HNSCC tumors correlate with decreased survival (36). Emerging evidence suggests that, in addition to TGF-, HB-EGF and/or AR are involved in GPCR ligand-mediated signaling. Activation of EGFR by GRP in lung cancer cells occurs via TGF- and HB-EGF, whereas in HNSCC cells TGF- and AR are involved (4, 37). Our findings suggest that only TGF-, and not HB-EGF or AR, is involved in EGFR activation by PGE2 or BK. Thus, depending on the type of GPCR ligand involved, autocrine release of TGF- either alone or along with other EGFR ligands, including HB-EGF or AR, may be increased. Autocrine release of EGFR ligands results from MMP activation in cells.
Membrane-bound EGFR proligands are processed and cleaved by metalloproteinases into functional ligands that bind to the receptor. Depending on the type of GPCR under investigation, EGFR proligands were reported to be activated by ADAM10, ADAM15, or ADAM17 in bladder and kidney cancer cells (38). We and others have previously shown that the TACE or ADAM17 is involved in GPCR-mediated activation of transmembrane EGFR ligand precursors pro-TGF-, pro-AR, and pro-HB-EGF (5, 19, 21, 38). Our current results corroborate these studies in that down-modulation of TACE by siRNA in HNSCC cells attenuated PGE2- and BK-mediated signaling events downstream of EGFR. In addition to TACE, our data show that Src family kinases are involved in PGE2- and BK-mediated signaling in HNSCC. This result is consistent with our previous finding that Src family kinases are involved in GRP ligand-mediated activation of EGFR in HNSCC (19). These cumulative findings implicate Src family kinases as a potential therapeutic target in HNSCC. Several Src tyrosine kinase inhibitors are under clinical development, including AZD0530, SKI-606, and BMS-354825 (39).
It is well established that activation of EGFR and downstream signaling molecules, including MAPK, results in increased proliferation and invasion of HNSCC cells (4, 40). PGE2 and BK have been implicated in the growth of colon and breast carcinoma, respectively (7, 8). Here, we have shown that GPCR ligands PGE2 and BK induce mitogenic effects in HNSCC cells. To determine the role of EGFR activation in GPCR-induced mitogenesis, we treated cells derived from EGFR KO mice with PGE2, BK, or EGF. Treatment of cells derived from WT littermates with either ligand modestly stimulated growth. However, EGF, PGE2, and BK failed to stimulate growth of EGFR KO cells. In addition, treatment of EGFR KO or WT cells with serum stimulated growth, showing that these cells can be stimulated to proliferate in vitro. These results suggest that EGFR tyrosine kinase activity primarily mediates the growth-stimulatory effects of GCPR in murine embryonic fibroblasts. Although this finding cannot be directly extrapolated to human HNSCC cells, it serves as a proof of principle that EGFR may mediate the proliferative effects of GPCR ligands PGE2 and BK. Inhibition of EGFR in HNSCC cell lines over 72 hours resulted in cell death, so it was not possible to elucidate the EGFR-independent effects of GPCR ligands on HNSCC cell proliferation. In addition to mitogenesis, GPCRs have been implicated in invasion of cancer cells (38). PGE2 and BK have been reported to induce invasion in cholangiocarcinoma and in bladder cancer cells, respectively (22, 41). Both PGE2 and BK induced invasion of HNSCC cells through Matrigel-coated Transwell chambers. Inhibition of EGFR with low doses of small-molecule inhibitors erlotinib or gefitinib abrogated GPCR ligand-mediated invasion of HNSCC cells. These results show that GPCRs promote migration and invasion of HNSCC cells via activation of the EGFR signaling axis. Thus, PGE2 and BK may stimulate MAPK phosphorylation independent of EGFR, although combined activation of EGFR and GPCR pathways is required for maximal invasiveness of HNSCC. Thus, PGE2 and BK receptors represent potential targets for HNSCC intervention strategies.
Several peptide inhibitors are being developed to target GPCRs. CU201 is a BK antagonist that is currently being tested in clinical trials for lung cancer (13). We determined that HNSCC cells were sensitive to low doses of CU201 in vitro. This dose is comparable with previous reports of micromolar doses of CU201 being cytotoxic in lung cancer cells (42). Despite promising antitumor effects in preclinical models, EGFR inhibitors tested in clinical trials have shown limited antitumor effects when administered as a monotherapy (43). Development of resistance to EGFR inhibition via the activation of downstream signaling molecules via alternate receptor pathways may explain the limited antitumor efficacy (44). In this report, we have shown activation of MAPK by PGE2 and BK via EGFR-independent pathways. Thus, combined targeting of GPCRs and EGFR would be more effective in abrogating tumor growth in HNSCC cells. Indeed, combined treatment with an EGFR tyrosine kinase inhibitor and the BK antagonist resulted in additive antitumor effects. Inhibition of the PGE2 synthesis pathway with COX-2 inhibitors has been reported to result in growth inhibition of lung cancer cells (45). Combined therapy with EGFR and COX-2 inhibitors resulted in antitumor effects in HNSCC cells (12). Here, we show that combined treatment of HNSCC cells with a small-molecule EGFR inhibitor and the nonselective COX inhibitor sulindac results in synergistic antitumor effects. Because GPCRs signal via both EGFR-dependent as well as EGFR-independent mechanisms, targeting both receptors simultaneously showed increased efficacy compared with inhibiting either receptor alone. These results support the development of therapeutic strategies that combine EGFR and GPCR targeting in HNSCC.
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Acknowledgments |
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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 with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8/ 3/06. Revised 9/29/06. Accepted 10/19/06.
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R. R. Seethala, W. E. Gooding, P. N. Handler, B. Collins, Q. Zhang, J. M. Siegfried, and J. R. Grandis Immunohistochemical Analysis of Phosphotyrosine Signal Transducer and Activator of Transcription 3 and Epidermal Growth Factor Receptor Autocrine Signaling Pathways in Head and Neck Cancers and Metastatic Lymph Nodes Clin. Cancer Res., March 1, 2008; 14(5): 1303 - 1309. [Abstract] [Full Text] [PDF]
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