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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
Departments of 1 Medicine/Medical Oncology, 2 Pathology, and 3 Preventive Medicine and Biometrics, University of Colorado Health Sciences Center and University of Colorado Cancer Center, Aurora, Colorado; 4 Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; and 5 Hamon Center for Therapeutic Oncology Research, Dallas, Texas
Requests for reprints: Samir E. Witta, Department of Medicine/Medical Oncology, University of Colorado Health Sciences Center, Campus Box 8117, P.O. Box 6511, Aurora, CO 80045. Phone: 303-724-3876; Fax: 303-724-3889; E-mail: Samir.Witta{at}uchsc.edu.
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Abstract |
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Introduction |
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EGFR interacts with the cell adhesion molecule E-cadherin (E-cad, CDH1; refs. 12–14). E-Cadherin modulates EGFR activation and signaling through its downstream targets. Whereas E-cadherin can inhibit ligand activation of EGFR (13), it enhances AKT activation in neighboring cells (14). High levels of phosphorylated AKT may also predict for response to EGFR TKIs (15). In lung cancer cell lines, E-cadherin expression is regulated by ß-catenin signaling and by zinc finger proteins including the Slug/Snail family, SIP1 and ZEB1 (TF-8, ZFHX1A, AREB6, and 
EF1; ref. 16). These transcription factors regulate the expression of genes via interaction with two 5'-CACCTG (E-box) promoter sequences (17). This regulation is facilitated by interaction with the transcriptional corepressor, CtBP, which recruits histone deacetylases (HDAC) leading to chromatin condensation and gene silencing (18). Inhibiting HDACs using trichostatin A in lung cancer cell lines led to reactivation of E-cadherin expression (16).
HDAC inhibitors are an emerging class of therapeutic agents that promote differentiation and apoptosis in hematologic and solid malignancies through chromatin remodeling and regulation of gene expression (19). MS-275 (Schering AG, Berlin, Germany), a benzamide HDAC inhibitor undergoing phase I investigation in hematologic and solid malignancies, leads to changes in histone acetylation that persist for several weeks following its administration (20).
In this study, we asked if E-cadherin expression was directly or indirectly related in response to EGFR TKIs. We found that E-cadherin and ZEB1 expression correlated with gefitinib sensitivity and restoring E-cadherin expression by transfection or HDAC inhibition resulted in an enhanced response to gefitinib. Clinical trials based on this observation are planned.
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Materials and Methods |
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The anti-E-cadherin antibody (mouse monoclonal, clone 36; Transduction Laboratories, Lexington, KY) was applied at a 1:100 dilution to sectioned paraffin-embedded cell lines. Antigen retrieval was done in citrate buffer using a Biocare Medical (Walnut Creek, CA) decloaking chamber. Peroxide blocking was preformed with 3% peroxide in absolute methanol. Blocking was done with Powerblock (Biogenics, San Ramon, CA) or avidin/biotin block. After incubation of primary antibodies for 1 hour at 37°C, the secondary antibody (Dako Biotinylated Multi-Link antimouse, immunoglobulin with 40% human serum) was applied for 30 minutes at room temperature. This was followed by application of streptavidin horseradish peroxidase enzyme complex and diaminobenzidine chromogen and hematoxylin counterstained.
RNA, primers, and quantitative real-time reverse transcription-PCR. Total RNA was prepared from NSCLC cell lines using the RNeasy kit (Qiagen, Valencia, CA). Quantitative real-time reverse transcription-PCR assays were done from 0.3 µg total RNA using the SYBR Green RT-PCR Kit (Qiagen) using a GeneAmp 5700 Sequence Detector (Applied Biosystems, Foster City, CA). Amplification data were analyzed by using GENEAMP 5700 SDS software, converted into cycle numbers at a set cycle threshold (Ct values) and quantified in relation to a standard. Human adult lung RNA (Clontech Lab., Inc., Mountain View, CA) was used as a standard at 20, 100, and 500 
g in all the experiments. To normalize for the amount of input cDNA, the quantified relative amount of the generated product was divided by the amount generated for ß-actin. All samples were done in triplicates. Primers were used as described, E-cadherin (16), ZEB1 (16), ß-actin, forward 5'-ATC-CAC-GAA-ACT-ACC-TTC-AAC-TC-3', reverse 5'-GAG-GAG-CAA-TGA-TCT-TGA-TCT-TC-3'.
Cell cycle analysis. NSCLC cells were plated at a density of 5 x 105 cells/well in six-well plates. Gefitinib was added to the medium after 24 hours, and the cells were incubated for another 48 hours. For the sequential treatment evaluation, MS-275 was added, followed by gefitinib 24 hours later and cells were incubated for an additional 48 hours. Cell death was evaluated using the Vybrant Apoptosis Assay Kit, propidium iodide (PI) or Annexin V-APC (V-13243 and A35110, respectively; Molecular Probes, Inc., Eugene, OR) and analyzed using flow cytometry according to the manufacturer's instructions.
Microarray analysis of gene expression. Following one round of in vitro transcription, 20 µg cRNA was hybridized with HG-U133 set microarrays and processed according to the manufacturer's protocol (Affymetrix, Foster City, CA). A MIAME checklist (22) containing extensive experimental details can be found in the online data supplement. Hybridization signals and detection calls were generated in BioConductor, using the gcrma and affy packages.
Statistical methods. Normal distribution of the variables was assessed by Shapiro-Wilk test. Reported correlations were done using Spearman's correlation coefficient. The comparisons between gene expression in the groups of resistant and sensitive cell lines were done with Mann-Whitney U test. For variables with normal distribution, we used paired t test (comparisons within the same cell line under two different conditions), independent t test (comparison between two different cell lines) and one-way ANOVA (comparisons between multiple cell lines). All reported P values are two-sided.
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Results |
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10 µmol/L, and the remaining 10 had an IC50 of 1 to 10 µmol/L.
This diverse growth response to gefitinib was used to identify genes differentially expressed in sensitive versus resistant cell lines. RNA isolated from 22 cell lines was used to interrogate Affymetrix oligonucleotide microarrays. Expression of E-cadherin and related molecules in the Wnt pathway (Wnt1, Wnt5A, Wnt5B, Wnt6, Wnt7A, frizzled, axin1, disheveled, GSK3 
-catenin, ß-catenin, and -catenin) were compared in the six sensitive and six resistant lines (Fig. 1A). Expression of E-cadherin and -catenin was significantly different between the sensitive and resistant cell lines (P = 0.004 and P = 0.016, respectively). When expression of E-cadherin and -catenin was evaluated in all the 22 cell lines, a significant correlation with gefitinib sensitivity was evident (E-cadherin, r = 0.76; P < 0.001; -catenin, r = 0.69; P < 0.001). The highest E-cadherin RNA expression was detected in the most sensitive cell line, H3255 (IC50 = 0.015 µmol/L) that harbors the EGFR mutation L858R (Table 1; refs. 6, 7). This correlation was confirmed in the 22 lines using real-time reverse transcription-PCR (r = 0.78, P < 0.001; Table 1). The data from the two methods of E-cadherin expression evaluation, real-time reverse transcription-PCR, and microarray analysis, correlated significantly (r = 0.85, P < 0.0001).
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E-cadherin expression is regulated by four zinc finger transcription factors: ZEB1, slug, snail and SIP1. Evaluation of the microarray data of the six sensitive cell lines and the six more resistant cell lines revealed that expression of ZEB1 significantly correlated with resistance to gefitinib (P = 0.004; Fig. 1A) and this correlation was maintained when data on all 22 lines were included (r = 0.75, P < 0.001; Table 1). Expression levels of ZEB1 in all 22 cell lines were reevaluated using real-time reverse transcription-PCR and the correlation was maintained (r = –0.76, P < 0.001; Table 1). Significant negative correlations were evident between ZEB1 expression and either E-cadherin (r = –0.82, P < 0.0001) or -catenin (r = –0.62, P = 0.002).
E-cadherin modulates gefitinib-induced apoptosis and EGFR activation in NSCLC. The correlation between E-cadherin and sensitivity to gefitinib led us to ask if E-cadherin could directly influence gefitinib responses. To address this question, an E-cadherin-negative, EGFR-positive gefitinib-resistant cell line, H157, was transfected with an E-cadherin expressing construct. Two stable G418-resistant clones were developed, H157-E-cad-3 (E3) and H157-E-cad-8 (E8), and E-cadherin expression was confirmed (Fig. 2, lanes 2-3).
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The effect of E-cadherin transfection on cell growth was evaluated with or without gefitinib treatment using the MTT assay. Reexpression of E-cadherin in the transfected cell lines, E3 and E8, resulted in a significant 30% (P = 0.002) and 45% (P < 0.001) decrease in growth compared with the parental cell line, respectively (Fig 3A). This effect was further enhanced in the presence of gefitinib (Fig. 3B). E-Cadherin transfectants, E3 and E8, became more sensitive (gefitinib IC50 of 6 and 3 µmol/L, respectively) to gefitinib compared with parental H157 cell line (IC50 = 12 µmol/L; Fig. 3B).
The effect of E-cadherin on cell death (apoptosis) in the presence and absence of gefitinib was evaluated using Annexin V and PI staining. Using Annexin V labeling, 3- and 9-fold increases in the ratio of apoptotic to viable cells was detected in E3 and E8, respectively, as compared with the control cell line H157-GFP (P = 0.083 and P = 0.013, respectively; Fig. 3C). Significant 6- and 13-fold increases in the ratio of apoptotic to viable cells were detected in the E3 and E8 cell lines compared with control cells when treated with gefitinib (P = 0.004 and P = 0.03, respectively; Fig. 3C). This indicated that expression of E-cadherin alone is able to drive some cell death and the apoptotic effect was further enhanced by gefitinib.
The apoptotic effect of gefitinib in the presence of E-cadherin was compared in the transfectant cell lines to that in cell lines sensitive to and resistant to gefitinib using PI staining (Fig. 3D). Treatment with 10 µmol/L gefitinib induced a 9-fold increase in the ratio of apoptotic to viable cells in the E8 transfectant as compared with control cells. At the same gefitinib concentration, there was a 2.4- to 6.3- and 63-fold increase in cell death in the gefitinib-sensitive with wild-type EGFR cell lines (H322, H358, and Calu3) or the EGFR mutant cell line H3255, respectively (Fig. 3D). Only slight apoptotic or necrotic effects were detected in the more resistant cell lines. This indicated that transfection of E-cadherin significantly enhances the apoptotic effect of gefitinib on resistant cell lines as compared with the gefitinib-resistant lines (P = 0.001). The degree of gefitinib sensitivity in the E-cadherin-transfected cell line was not significantly different from that in the wild-type sensitive cell lines (P = 0.102) or in the EGFR mutant cell line, H3255 (P = 0.387).
HDAC inhibitors reverse resistance to gefitinib. We tested whether the HDAC inhibitor MS-275 could increase expression of E-cadherin and EGFR, and thus increase response to gefitinib. E-Cadherin expression increased by 26- to 190-fold in the gefitinib-resistant NSCLC cell lines H157, H520, and H1703 following 24-hour exposure to MS-275 (Fig. 4A). In H520 cells that express neither E-cadherin nor EGFR, expression of EGFR increased by 27-fold after MS-275 exposure (data not shown).
The MS-275 IC50 in the gefitinib-resistant lines H157, H460, H520, and H1703 was between 0.5 and 4 µmol/L (Fig. 4B). The H157 cell line was treated separately with MS-275, gefitinib, or the sequential combination of MS-275 followed by gefitinib 24 hours later and evaluated for cell growth using MTT assay (Fig. 4C). An 81% inhibition in cell growth was detected with 1 µmol/L of gefitinib when H157 was pretreated with 1 µmol/L of MS-275 (from 99% to 18%; Fig. 1C). A synergistic effect was detected with the sequential use of MS-275 followed by gefitinib in this cell line. We calculated the combination index for each set of concentrations using the isobologram method (23). A combination index of <1, indicating synergy, was detected in the combination of gefitinib with MS-275 at most concentrations of each drug (Fig. 4D).
Next, we evaluated the effect of pretreatment with MS-275 on the apoptotic effect of gefitinib in the gefitinib-resistant NSCLC cell lines H157 and H520. A synergistic effect was detected with the sequential use of MS-275 followed by gefitinib in both of these cell lines. Increasing doses of MS-275 (0.5-4 µmol/L) resulted in a small increase in cell death in both H157 and H520 (4- to 6.7-fold and 2.4- to 4.8-fold increase, respectively; Fig. 5A and B). Similarly, treatment of these cells with increasing doses of gefitinib (10-14 µmol/L) resulted in almost no effect on apoptosis in these two cell lines (0.9- to 1.1-fold and 1.2- to 1.6-fold increase, respectively) compared with the control (Fig. 5A and B). These doses of gefitinib were chosen because they fall within IC25-75 for growth inhibition in the tested cell lines. When the two cell lines were treated with increasing doses of MS-275 for 24 hours prior to treatment with gefitinib, a significant and synergistic increase in cell death was detected. When the H157 cell line was treated with MS275 at 4 µmol/L followed by gefitinib at 10 to 14 µmol/L, a 36- to 50-fold increase in cell death was evident (Fig. 5A). In the H157 cell line, the apoptotic effect of MS-275 and gefitinib combination was similar to that of gefitinib in the mutant cell line H3255 (Fig. 5A). Similar treatments led to a 16- to 22-fold increase of cell death in the H520 cell line (Fig. 5B). Gefitinib and MS-275 produced additive to synergistic effects at nearly all of the concentrations tested.
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Discussion |
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It is not fully understood why a subset of NSCLC EGFR-expressing tumors progress on treatment with EGFR TKI. EGFR TK mutations or the presence of EGFR-interacting molecules may predispose tumors for the action of EGFR TKI. A recent study showed that ErbB3 couples EGFR to the phosphoinositide-3-kinase/Akt pathway in gefitinib-sensitive NSCLC cell lines harboring wild-type and mutant EGFRs (35). In this study, we show that E-cadherin augments EGFR activation by EGF, which could serve as another way to regulate downstream events in the EGFR signaling pathway.
The value of identifying differentially expressed genes and proteins resides not only in developing biomarkers but also in strategies to overcome resistance to EGFR inhibitors. We evaluated the effect of E-cadherin on response to gefitinib in a cell line that expresses EGFR and is gefitinib-resistant (H157). Transfection of E-cadherin resulted in an increased activation of EGFR by EGF (Fig. 2). Recent studies indicated that the most EGFR TKI-sensitive cell lines have higher levels of EGFR activation (6), suggesting that expression of E-cadherin in cell lines increases dependence on EGFR for growth and survival.
Increasing E-cadherin expression both by transfection of E-cadherin and by exposure to MS-275 increased sensitivity to gefitinib to levels observed in sensitive NSCLC cell lines (Figs. 3-5). E-Cadherin transfection resulted in a 2- and 3-fold decrease in the IC50 of gefitinib and an apoptotic effect similar to that in wild-type gefitinib-sensitive cell lines (Fig. 3C and D). In lung cancer cells, we suggest that E-cadherin expression is not only a potential marker of response to EGFR inhibitors but also plays a role in the mechanism underlying response to these drugs.
Epigenetic changes leading to gene silencing are primary mechanisms modulating gene expression in cancerous cells (36). Histone acetylation and deacetylation is one mechanism that permits or halts gene expression, respectively (37). HDAC inhibitors act to restore gene expression leading to growth arrest, differentiation, and apoptosis of transformed cells (38). E-Cadherin expression is regulated by HDACs and its expression is restored with HDAC inhibitors (16). E-Cadherin can also be regulated by tumor acquired DNA promoter methylation, however, E-cadherin only undergoes methylation in 
18% of NSCLCs indicating that histone acetylation is probably the major mechanism of inactivation of E-cadherin expression in these tumors (39).
These findings have made it possible to test a clinically applicable treatment that would enhance E-cadherin expression and test the influence on response to gefitinib. We found a synergistic effect on growth inhibition and apoptosis from sequential treatment with MS-275 and gefitinib. In the presence of 1 µmol/L MS-275, cell line growth was inhibited by 81% with 1 µmol/L of gefitinib, a dose that does not lead to any growth inhibition in the absence of MS-275 (Fig. 4C). Those concentrations are clinically relevant as the maximum plasma concentrations (Cmax) achievable were 0.25 to 5 µmol/L for gefitinib and 0.5 to 2 µmol/L for MS-275 (20, 40). Pretreatment with MS275 also resulted in a 16- to 50-fold increase in apoptosis in the gefitinib-resistant cell lines tested. This increase in cell death was similar to what was detected in the mutant cell line H3255 treated with gefitinib alone (Fig. 5). The magnitude of increase in cell death exceeds what we detected with the ectopic expression of E-cadherin in H157 (Fig. 3D), indicating that other favorable genetic changes may also predispose these cell lines for the action of gefitinib or increase their apoptosis following treatment with MS275. This enhancement in the apoptotic effect of gefitinib was detected even in a cell line that lacks EGFR expression. However, this response could be explained by restoring EGFR expression by the pretreatment with MS275. HDACs affect many pathways (41–43), including those that favorably affect tumorigenesis such as the transforming growth factor-ß RI and RII and p21WAF1/Cip1. We confirmed the activation of these molecules by MS275 in gefitinib-resistant NSCLC cell lines (data not shown). This indicates that the synergistic effect of MS275 and gefitinib in the NSCLC cell lines could be, in part, a result of enhancing response to EGFR inhibitors by expressing molecules such as E-cadherin, and in part, affecting other pathways. This enhanced antitumor effect was previously reported when an HDAC inhibitor, NVP-LAQ842 was combined with a vascular endothelial growth factor receptor TKI, PTK787/ZK222584 (44).
In summary, we show that the cell adhesion molecule E-cadherin predicts and influences response to gefitinib in NSCLC cell lines and pretreatment of cells with the HDAC inhibitor MS-275 increases response to gefitinib. Drug concentrations that led to synergistic effects on cell growth are clinically achievable. Clinical trials are planned to evaluate the sequential combination of HDAC inhibitors and EGFR TKI in patients with advanced stage NSCLC.
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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 6/ 7/05. Revised 10/24/05. Accepted 11/ 1/05.
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