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Molecular Cancer Research 3:271-275 (2005)
© 2005 American Association for Cancer Research

Cell Cycle, Cell Death, and Senescence

E1A Specifically Enhances Sensitivity to Topoisomerase II{alpha} Targeting Anticancer Drug by Up-Regulating the Promoter Activity

Zhichao Zhou, Hui Guan and Eugenie S. Kleinerman

Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Eugenie S. Kleinerman, Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Unit 87, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8110; Fax: 713-794-5042. E-mail: ekleiner{at}mail.mdanderson.org


   Abstract
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 Notes
 Abstract
Introduction
 Results
 Discussion
 Materials and Methods
 Acknowledgements
 References
 
DNA topoisomerases I and II (topo I and II) are nuclear enzymes involved in cellular replication and are targets for several anticancer drugs. We showed previously that E1A gene transfer enhanced the sensitivity of Ewing's sarcoma cells to the topo II{alpha} targeting agents etoposide and Adriamycin in vitro and in vivo. To determine whether this effect was specific for topo II{alpha}, we investigated the effect of E1A gene transfer on cell sensitivity to agents that target topo I and IIß. Transfecting TC71 human Ewing's sarcoma cells with an adenoviral vector containing the E1A gene enhanced their sensitivity to the topo II{alpha} targeting agents etoposide (16-fold) and Adriamycin (8-fold). By contrast, E1A gene transfer did not affect cellular sensitivity to either amsacrine or camptothecin. Western blot analysis indicated that topo II{alpha} protein levels increased 3.1-fold after E1A gene transfer, but topo I and IIß protein levels did not change. A plasmid containing topo II{alpha} gene promoter with luciferase reporter gene was constructed to determine the effects of E1A gene transfer on the activity of the topo II{alpha} promoter. E1A increased the activity of the topo II{alpha} gene promoter by 3.5-fold relative to that of cells transfected with Ad-ß-gal. These results suggest that elevated topo II{alpha} protein levels and enhanced sensitivity to topo II{alpha} targeting agents were secondary to a direct effect of E1A on the topo II{alpha} promoter. Combining E1A gene therapy with topo II{alpha} targeting anticancer drugs may therefore have therapeutic benefit by increasing tumor cell sensitivity.


   Introduction
Top
 Notes
 Abstract
 Introduction
Results
 Discussion
 Materials and Methods
 Acknowledgements
 References
 
Topoisomerases are nuclear enzymes that control DNA topology, cell differentiation, and cell replication. Many anticancer drugs stabilize the covalent complex formed between DNA and the topoisomerase enzymes, thereby initiating a biochemical cascade leading to cell death (1, 2). Resistance to chemotherapy has been shown to involve several different mechanisms, including alteration of topoisomerases (3-5). Topoisomerases have several different isoforms [i.e., topoisomerase I, II{alpha}, and IIß (topo I, II{alpha}, and IIß)]. Camptothecin and topotecan target topo I, etoposide (VP-16) and Adriamycin target topo II{alpha}, and amsacrine targets topo IIß (6, 7). We showed previously that E1A gene transfer into human Ewing's sarcoma cells increased cellular sensitivity to VP-16 and Adriamycin in vitro and in vivo (8, 9). This increased sensitivity was shown to be secondary to an increase in topo II{alpha} expression. To ascertain whether this effect on topo II{alpha} was specific and to further determine the mechanism responsible for enhanced topo II{alpha} expression, we investigated the effect of the E1A gene on cell sensitivity to topo I and IIß targeting agents and on the activity of the topo II{alpha} promoter. We found that E1A gene transfer into TC71 human Ewing's sarcoma cells enhanced their sensitivity to topo II{alpha} targeting drugs but not to agents that target topo I or IIß. Topo II{alpha} protein expression and the activity of the topo II{alpha} promoter were also increased by E1A gene transfer. These results suggest that in addition to acting as a transcriptional repressor of HER-2/neu the E1A gene may act as a transcriptional promoter of topo II{alpha}.


   Results
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 Notes
 Abstract
 Introduction
 Results
Discussion
 Materials and Methods
 Acknowledgements
 References
 
Effect of E1A on the Sensitivity of TC71 Cells to Agents That Target Topo II{alpha}, IIß, or I
Our first step was to confirm that E1A sensitized TC71 cells to the topo II{alpha} targeting agents VP-16 and Adriamycin. Transfection with the E1A gene increased cellular sensitivity to VP-16 by 16-fold (IC50, 90 nmol/L versus 1.5 µmol/L), whereas transfection with Ad-ß-gal did not alter cell sensitivity (IC50, 1.3 µmol/L; Fig. 1A). E1A gene transfer also enhanced the sensitivity of TC71 cells to Adriamycin (IC50, 12 versus 100 nmol/L; Fig. 1B). By contrast, E1A transfer did not affect cellular sensitivity to amsacrine (a topo IIß targeting agent) or camptothecin (a topo I targeting agent; Fig. 1C and D). Results for all drugs are summarized in Table 1. The IC50 for amsacrine was 2.1 versus 2.0 µmol/L with E1A and 3.0 versus 2.5 µmol/L with E1A for camptothecin.



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  		FIGURE 1. E1A enhanced the sensitivity of TC71 cells to VP-16 and Adriamycin but not to amsacrine or camptothecin. TC71 cells were treated with different concentrations of VP-16 (VP16; A), Adriamycin (ADR; B), amsacrine (AMSA; C), or camptothecin (Campt; D) with or without Ad-E1A or Ad-ß-gal as indicated. Cytostasis was quantified using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Points, mean of three independent experiments; bars, SD.

 

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  		Table 1. Effects of E1A on Cell Sensitivity to VP-16, Adriamycin, Amsacrine, and Camptothecin

 
Effect of E1A on Topo II{alpha},IIß, and I Protein Expression
Western blotting analyses indicated that topo II{alpha} protein levels increased by 3.1-fold after transfection with E1A (Fig. 2, top). In contrast, transfection with Ad-ß-gal did not affect topo II{alpha} protein expression. Transfection with E1A did not affect topo IIß (Fig. 2, middle) or topo I (Fig. 2, bottom) protein levels compared with cells transfected with Ad-ß-gal (Fig. 2). These results suggest that the E1A gene specifically increased cellular topo II{alpha} protein levels and that this effect led to their sensitivity to the topo II{alpha} targeting drugs VP-16 and Adriamycin.



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  		FIGURE 2. E1A increased topo II{alpha} protein expression but not that of topo IIß or I. TC71 cells were treated with PBS (lane 1), Ad-E1A (lane 2), or Ad-ß-gal (lane 3) for 48 hours. Cellular protein was extracted and subjected to electrophoresis on SDS-PAGE gel. Expression of topo II{alpha} (top), topo IIß (middle), and topo I (bottom) proteins was detected by Western blot using specific antibodies. Densitometric analysis of each band was normalized with a ß-actin loading control. Relative expression levels were calculated in comparison with the protein levels in the TC71 control cells.

 
Effect of E1A on Topo II{alpha} Promoter Activity
After finding that E1A gene transfer up-regulated topo II{alpha} expression and protein production, we next investigated the effects of the E1A gene on the topo II{alpha} promoter by using pGL-topo II{alpha}-557, a vector containing the topo II{alpha} gene promoter with a luciferase reporter gene. Transfection with adenoviral vector containing the E1A gene (Ad-E1A) increased the luciferase activity by 3.5-fold compared with Ad-ß-gal. Following treatment with Cdk2/cyclin inhibitory peptide II, which inactivated E2F-1 transcript factor function (10), Ad-E1A did not significantly alter the topo II{alpha} promoter activity (Fig. 3, top). We verified the specificity of this activity by testing the effect of E1A on the Fas promoter in cells transfected with FPR-Fas-Luc. Treatment of those cells with Ad-E1A did not change Fas promoter activity. Transfer of the IL-12 gene using Ad-IL-12 served as our positive control (11) and resulted in increased Fas promoter activity (Fig. 3, bottom).



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  		FIGURE 3. E1A gene transfer increased topo II{alpha} promoter activity. TC71 cells were treated with or without Cdk2 inhibitory peptide II and cotransfected with the pGL-topo II{alpha}-557 vector (top) or FPR-Fas-Luc vector (bottom) with pRL-TK Renilla luciferase vector. Six hours later, the cells were treated with PBS, Ad-E1A, Ad-ß-gal, or Ad-IL-12 as indicated. Cells were then harvested, lysed, and assayed for luciferase activity. Relative luciferase activity was calculated in comparison with that of control cells. Columns, mean of three independent experiments; bars, SD.

 

   Discussion
Top
 Notes
 Abstract
 Introduction
 Results
 Discussion
Materials and Methods
 Acknowledgements
 References
 
In the present study, we showed that E1A gene transfer specifically enhanced the sensitivity of human Ewing's sarcoma cells to the topo II{alpha} targeting drugs VP-16 and Adriamycin. E1A up-regulated both topo II{alpha} expression and protein production but did not affect topo IIß or I protein levels and did not alter cell sensitivity to either amsacrine (targets topo IIß) or camptothecin (targets topo I). We further showed that E1A specifically enhanced the activity of the topo II{alpha} promoter, indicating that E1A up-regulates topo II{alpha} expression through a mechanism involving the promoter. The exact pathway by which E1A stimulates topo II{alpha} promoter activity is unclear, but recent findings suggest that E1A gene expression is associated with the expression of E2F-1 (12), a transcription factor that regulates topo II{alpha} (13). Up-regulation of topo II{alpha} promoter activity by E1A is via the E2F-1 pathway. Following blockage of E2F-1 activity by Cdk2 inhibitor, E1A did not alter topo II{alpha} promoter activity (Fig. 3). The Rb-binding domain of E1A is required for enhancement of sensitivity of cells to topo II{alpha} targeting drugs (14). Sensitivity to VP16 was not enhanced in cells with mutated E1A in the Rb-binding region or following inactivation of E2F-1 function by Cdk2 inhibitor (data not shown). These results imply that there may be a link between E1A and the up-regulation of the topo II{alpha} promoter that involves E2F-1.

E1A is a multifunctional oncogene that has been shown by us and others to down-regulate HER-2/neu (8, 9, 15). We showed previously that the intratumoral injection of E1A in nude mice down-regulated HER-2/neu in Ewing's sarcoma tumors in vivo and enhanced tumor sensitivity to VP-16 (9). Findings from our current study suggest that this enhanced sensitivity to VP-16 may be independent of HER-2/neu. Indeed, treatment of TC71 cells in vitro or in vivo with Herceptin (trastuzumab) led to decreased HER-2/neu expression but had no effect on either topo II{alpha} expression or sensitivity to VP-16 (16). Therefore, HER-2/neu down-regulation does not seem to be directly lined to enhanced topo II{alpha} expression. Whereas E1A affects both, Herceptin only affects HER-2/neu.

Cellular resistance to VP-16 has been linked to decreased cellular topo II{alpha} protein levels (17). Restoration of topo II{alpha} protein levels by transfection with an adenoviral vector containing the topo II{alpha} gene led to enhanced cellular sensitivity to VP-16 (18). E1A gene therapy is currently in clinical trials for patients with breast or ovarian cancer in which the tumors overexpress HER-2/neu (19). Our findings suggest that E1A gene therapy may prove beneficial for tumors that do not overexpress HER-2/neu by virtue of its ability to also up-regulate the topo II{alpha} promoter, leading to increased topo II{alpha} expression and increased topo II{alpha} protein production, thereby increasing the drug target. Presumably, these effects will in turn enhance tumor sensitivity to topo II{alpha} targeting agents, such as Adriamycin and VP-16.


   Materials and Methods
Top
 Notes
 Abstract
 Introduction
 Results
 Discussion
 Materials and Methods
Acknowledgements
 References
 
Cell Line
TC71 human Ewing's sarcoma cells (kindly provided by Dr. T. Triche, University of Southern California, Los Angeles, CA) were cultured in Eagle's modified essential medium with 10% fetal bovine serum, 2 mmol/L L-glutamine, 1 mmol/L sodium pyruvate, 1x nonessential amino acid, and 2x MEM vitamin solution (Life Technologies, Inc., Grand Island, NY). This cell line was screened with a Mycoplasma Plus PCR Primer Set (Stratagene, La Jolla, CA) and found to be free of Mycoplasma.

Recombinant Adenovirus
Ad-E1A (kindly provided by Dr. M-C. Hung, Department of Molecular and Cellular Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX) is an adenovirus type 5–based vector that contains E1A but lacks E1B and E3 (15). The control adenovirus, Ad-ß-gal, is an adenovirus type 5 that lacks E1A, E1B, and E3 but contains ß-galactosidase. Both of these recombinant replication-deficient adenoviral vectors were propagated in human embryonic kidney 293 cells as described previously (20). The viruses were purified twice by cesium chloride gradient ultracentrifugation and then dialyzed and titrated using standard methods. Cells in logarithmic growth phase were infected with adenovirus at 10 plaque-forming units/cell for 48 hours and then treated as indicated for the various experiments.

Cytostasis Assay
TC71 cells were seeded onto 96-well cell culture plates (5,000 per well) and allowed to adhere overnight before being infected with Ad-E1A or Ad-ß-gal. Cells were then treated with various concentrations of VP-16, Adriamycin, camptothecin, or amsacrine for 24 hours (Sigma Chemical Co., St. Louis, MO). Antiproliferative activity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay as described previously (21). Each measurement was done in triplicate and each experiment was done at least thrice to determine the mean and SD.

Western Blot Analysis
TC71 cells were seeded on 100 mm dishes 24 hours (2 x 106 cells per dish) before treatment. The cells were then re-fed and treated with Ad-E1A or Ad-ß-gal at 10 plaque-forming units/cell for 48 hours. Cells were washed with cold PBS and lysed with buffer consisting of 50 mmol/L Tris-HCl (pH 8.0), 425 mmol/L NaCl, 1% NP40, 0.5% sodium deoxychlolate, 0.1% SDS, 10 mmol/L ß-mercaptoethanol, and the protease inhibitors aprotinin (2 µg/mL), leupeptin (2 µg/mL), pepstatin A (1 µg/mL), and phenylmethysulfonyl fluoride (100 µg/mL). Solubilized protein (50 µg) was run on a 7.5% SDS-PAGE gel and transferred to a Hybond enhanced chemiluminescence nitrocellulose membrane (Amersham Pharmacia Biotech, Piscataway, NJ). Antibodies to human topo II{alpha}, topo I (TopoGEN, Inc., Columbus, OH), topo IIß (BD Bioscience PharMingen, Inc., San Diego, CA), and ß-actin were used for protein detection with the enhanced chemiluminescence analysis system.

Topo II{alpha} Promoter Vector Construction
The topo II{alpha} promoter vector pGL-topo II{alpha}-557 (kindly provided by Dr. D.P. Suttle, University of Tennessee Health Science Center, Memphis, TN) was created by subcloning the PCR product containing the topo II{alpha} promoter into a pGL2 basic vector linking upstream of the luciferase gene. Plasmid DNA was purified with the Qiagen plasmid purification kit (Valencia, CA) and confirmed by restriction enzyme analysis (22). The Fas promoter FPR-Fas-Luc vector (23) used to verify the specificity of the effect on the topo II{alpha} promoter was kindly provided by Dr. L.B. Owen (University of California, Riverside, CA).

Luciferase Assay
TC71 cells were plated in six-well plates at 2 x 105 cells per well. After 24 hours, fresh medium was replaced. Cells were treated with or without 10 µmol/L Cdk2/cyclin inhibitory peptide II (Calbiochem, La Jolla, CA) for 4 hours; then, cells were transfected with 1 µg of either the pGL-topo II{alpha}-557 plasmid or the FPR-Fas-Luc vector together with 1 µg Renilla luciferase vector pRL-TK by using FuGene 6 transfection reagents (Roche Diagnostics Corp., Indianapolis, IN). Six hours later, the cells were treated with Ad-E1A, Ad-ß-gal, or Ad-IL-12, which was used as a positive control for the Fas promoter (11) at 10 plaque-forming units/cell for 48 hours. Cells were harvested, lysed in 1x passive lysis buffer (Promega, Madison, WI), and gently shaken on a platform shaker for 15 minutes at room temperature. The cell lysates (20 µL) were then transferred into microcentrifuge tubes. Luciferase activity was quantified with a luminometer in a Dual-Luciferase Reporter Assay System (Promega). The relative luciferase activity for each sample was adjusted with an internal control for Renilla luciferase activity. Each measurement was done in triplicate. The mean and SD for each sample were calculated from three different experiments.


   Acknowledgements
Top
 Notes
 Abstract
 Introduction
 Results
 Discussion
 Materials and Methods
 Acknowledgements
References
 
We thank Dr. D.P. Suttle for providing the topo II{alpha} promoter vector and M-C. Hung for the Ad-E1A vector.


   Notes
Top
 Notes
Abstract
 Introduction
 Results
 Discussion
 Materials and Methods
 Acknowledgements
 References
 
Grant support: National Cancer Institute grant CA82606 (E.S. Kleinerman) and Cancer Center Support core grant CA16672 (The University of Texas M.D. Anderson Cancer Center).

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 10/18/04; revised 3/ 9/05; accepted 3/22/05.


   References
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 Notes
 Abstract
 Introduction
 Results
 Discussion
 Materials and Methods
 Acknowledgements
 References
 

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