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[Cancer Research 61, 935-938, February 1, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

p73{alpha} Overexpression Is Associated with Resistance to Treatment with DNA-damaging Agents in a Human Ovarian Cancer Cell Line1

Faina Vikhanskaya2, Sergio Marchini2, Mirko Marabese, Emanuela Galliera and Massimo Broggini3

Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri," 20157 Milan, Italy


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
We examined the consequences of p73{alpha} overexpression on gene expression and cellular response to anticancer agents in clones from the human ovarian cancer cell line A2780. Using microarray filters, the expression of 588 genes in two clones overexpressing p73{alpha} (A2780/p73.4 and A2780/p73.5) in comparison with empty vector-transfected cells was evaluated. There were clear differences in gene expression profiles. Both of the clones showed a marked increase in the expression of genes involved in DNA repair, including genes participating in nucleotide excision repair and mismatch repair. This was confirmed by reverse transcription-PCR and Northern blot analysis and was associated with an increase in the ability of p73{alpha}-expressing clones to repair two different DDP (cis-dichlorodiammine platinum)-damaged plasmids in a host reactivation assay. p73{alpha} overexpressing clones were less sensitive than parental cells to alkylating agents treatment or UV radiation but equally sensitive to the topoisomerase I inhibitor topotecan, which indicated that the increase in expression of DNA repair genes has implications for the response to DNA damaging agents.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The p53-related gene p73 shares high sequence homology with p53 in critical regions including the DNA binding domain (1) . As a result, p73 can transcriptionally activate p53 target genes such as p21, BAX, 14-3-3{varsigma}, and GADD45, although with different specificity (1 , 2) . Although in some cell lines in vitro, the introduction of p73 arrests the growth (1 , 3) , the role of p73 as a tumor suppressor is still uncertain. Mutational analysis of p73 gene in different human cancers did not reveal any significant tumor-associated mutations (4, 5, 6) ; p73 knock-out mice show specific neuronal disorders and a defective immunological response (7) but do not develop spontaneous tumors, which are invariably found in p53 null mice (8) .

In certain tumor types, the expression of p73 is greater than in normal tissue (4 , 9, 10, 11) . This could drastically influence the cell responses to stress, because p73{alpha} overexpression can reduce the transcriptional activity of p53 (12 , 13) .

p53 is one of the important factors in determining cellular sensitivity to anticancer agents (14 , 15) . The role of p73, if any, in cellular responses to stress still needs to be elucidated.

We investigated the consequences of p73{alpha} overexpression using clones established after transfection of p73{alpha} in the wild-type p53-expressing human ovarian cancer cell line A2780; we analyzed changes in gene expression and the response of these clones to different chemical and physical DNA-damaging agents.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Cell Culture and Treatment.
Clones derived from the human ovarian carcinoma cell lines A2780, A2780/pCDNA3, A2780/p73.4, and A2780/p73.5 were obtained and grown as reported previously (12) . DDP4 was obtained from Bristol Myers Squibb (Syracuse, NY). Topotecan was obtained from Smith, Kline & Beecham (Brentford, United Kingdom) and MNNG was purchased from Sigma (Milan, Italy). For clonogenic assay, cells were plated at 250 cells/well. After treatment with different drug concentrations or UV doses, plates were incubated for 8–10 days in drug-free medium, and the number of colonies formed were stained with 10% cristal violet in 20% ethanol and automatically counted on an image analyzer (Immagini & Computer, Milan, Italy). The data of the survival curves were plotted as percentages of untreated controls. IC50 values were calculated from three-four independent experiments, each consisting of at least three replicates. Plating efficiency was ~80% in all three of the cell lines.

Microarray Analysis of Gene Expression.
Total RNA was isolated from exponentially growing cells using the Qiamp RNA kit (Qiagen, Milan, Italy) followed by in column treatment with RNase-free DNase (Qiagen). Five µg of total RNA were retrotranscribed to cDNAs in the presence of [32P]dATP, (Amersham, Milan, Italy) using a mixture of specific oligonucleotides (Clontech, Firenze, Italy). Equal amounts of labeled cDNAs were hybridized to filters containing 588 genes (Clontech; ATLAS human cancer). After washing as recommended, filters were autoradiographed and gene expression patterns evaluated using the ATLAS Image Software 1.0 (Clontech).

RT-PCR and Northern Blot Analysis.
Semiquantitative RT-PCR analysis was done using the RT-PCR core kit (Perkin-Elmer, Milan, Italy) with a reduced number of cycles and coamplification of actin as internal control. Northern blot analysis was done according to standard procedures (16) . Filters were hybridized with 32P-labeled cDNAs using a Rediprime kit (Amersham). Hybridizations were done in 50% formamide, 10% dextran sulfate, 1% SDS, 1 M NaCl at 42°C for 16 h, followed by two 10-min washes at room temperature with 2x SSC and one 30-min wash at 65°C in 2x SSC-1% SDS.

Cell Reactivation of a DDP-damaged Plasmid.
Purified pGL2 and pG13Luc plasmids were treated with DDP (20 or 200 µM) for 10 min at room temperature, as described previously (17) , and were precipitated and washed in 70% ethanol. Cells were transfected with 5 µg of pGL2 or pG13Luc and 0.5 µg of untreated pRL-SV40 used for internal normalization with the calcium phosphate technique. Reporter gene activities were evaluated after 24 h using the Dual Luciferase system (Promega, Milan, Italy). Results are expressed as the percentage of the control luciferase reported activity normalized by the renilla activity value. The mean ± SD of three independent experiments is shown.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Overexpression of p73{alpha} did not affect the growth rate of A2780 cells; in fact A2780/p73.4 and A2780/p73.5 showed doubling times of 40 and 50 h respectively, not significantly different from the 42 h for empty vector-transfected cells (data not shown).

The gene expression profile, analyzed using microarray technology in the clones overexpressing p73{alpha}, showed a clear difference compared with empty vector-transfected cells (Fig. 1)Citation . As it can be seen from this figure, many genes showed a more than 2-fold difference in the expression in the two clones when compared with empty vector-transfected cells.



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  		Fig. 1. Scatter plot of log-transformed expression data for A2780/p73.4 and A2780/pCDNA3 cells (left panel) and for A2780/p73.5 and A2780/pCDNA3 cells (right panel). Solid line, identity between the two cell populations. Points below or above the two dashed lines, those for which a >2-fold change in gene expression has been found.

 
A2780/p73.4 and A2780/p73.5 clones showed a similar level of p73 mRNA, respectively, 10 and 11 times higher than in the empty vector transfected cells (Table 1)Citation . Similarly, the basal level of genes known to be transcriptionally responsive to p53 (and to p73) and present in the filter, such as GADD45, BAX , and some of the PIG genes were higher in the two clones than in control cells (Table 1)Citation . These findings confirmed the previously reported increase in basal levels of p53-responsive genes in these clones, determined by Northern blot analysis (12) and provide a good internal control for the analysis of gene expression patterns. The most striking changes in gene expression profile were detected in the DNA repair gene section, in which both clones showed an increase in the expression of many genes including members of the NER and MMR pathways, GADD45, DNA-PK, and ATM (Table 1)Citation .


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  		Table 1 Quantitative changes in gene expression in A2780/p73.4 and A2780/p73.5 cells compared with controls

 
For the other groups of genes on the filter, we could not pick up any clear change in the overall pattern of expression. Although we detected changes in the expression of some genes involved either in cell cycle regulation or in apoptosis or belonging to the family of growth factors, there was no similar change in gene expression between the two clones, as was found for DNA repair and DNA damage response genes (Table 1)Citation . Some differences were also found when we analyzed the expression of genes involved in cell-cell interactions. For some of these genes, in fact, A2780/p73.4 showed a relatively modest decrease in the levels compared with control cells, whereas A2780/p73.5 cells showed an increase (Table 1)Citation ; the gene expression data obtained for the two p73 overexpressing clones and not reported here are available on the Internet.5 Overall we could detect changes in gene expression (with values greater than 2) in ~22 and 16% of genes for A2780/p73.4 and A2780/p73.5, respectively. Thirty-five (6%) of 588 genes were consistently changed in both of the clones, and the majority of these were up-regulated.

For some of the genes whose expression was changed by microarray analysis (including XPA, XPG, XPD, DNA-PK, b-RAF), we confirmed the changes by using RT/PCR and/or Northern blot analysis (data not shown).

We used the host cell reactivation assay to evaluate whether the marked changes in the expression of genes involved in DNA repair pathways found in both of the p73-expressing clones could result in differences in their DNA repair ability. Two DDP-damaged luciferase-encoding plasmids, one under the control of SV40 promoter and the other under the control of 13 copies of a strong p53-responsive element, were transfected in A2780/pCDNA3, A2780/p73.4, or A2780/p73.5 cells. Fig. 2Citation reports the relative luciferase activity with the two plasmids in these cell lines. The two p73-transfected clones seemed to repair both of the DDP-damaged plasmids better, in agreement with the levels of expression for the DNA repair genes. We found more extensive repair with the plasmid containing the p53-responsive element, as shown previously (18) .



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  		Fig. 2. Host cell reactivation assay in A2780/pCDNA3 ({blacksquare}), A2780/p73.4 (•), and A2780/p73.5 ({circ}) cells. Values represent the mean ± SD of at least three determinations.

 
Considering the reported effects of p73 overexpression on p53 function in A2780 cells (12) and the gene expression and DNA repair data obtained here, we checked whether this could translate in differences in the cellular responses to DNA-damaging agents. Fig. 3ACitation reports four independent experiments performed treating the three cell lines with DDP. Both of the p73-overexpressing clones were less sensitive than empty vector-transfected cells with IC50s approximately 3 and 4 times higher for A2780/p73.4 and A2780/p73.5 clones, respectively, than for A2780/pCDNA3 cells. Similarly, both of the p73-overexpressing clones showed lower sensitivity (2- to 3-fold) to another type of DNA damage such as that induced by UV radiation (Fig. 3B)Citation or by treatment with a methylating agent such as MNNG (Fig. 3C)Citation . A drug not directly acting on DNA, such as the topoisomerase I inhibitor topotecan, showed, instead, similar activity in the two clones and in the empty vector-transfected cells (Fig. 3D)Citation .



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  		Fig. 3. Cell growth inhibition induced by DDP (A), UV (B), MNNG (C), and topotecan (D) in empty vector-transfected and p73-overexpressing clones. Values reported are the mean ± SD from at least three independent experiments, each consisting of four replicates. {blacksquare}, A2780/pCDNA3; {square}, A2780/p73.4; {circ}, A2780/p73.5. Cells were treated for 2 h with DDP and for 1 h with MNNG and topotecan.

 
Finally we checked whether the expression of some of the genes involved in DNA repair was still higher in p73-overexpressing clones after treatment with DNA damaging agents. Fig. 4Citation reports the results obtained with GADD45, XPD, XPB, and XPG. In general the differences in expression found in the basal levels were maintained evaluating the levels 24 h after treatment with both DDP (right panel) and UV (left panel). In particular, for GADD45, we found an increased expression after DNA damage both in parental and p73-overespressing cells. The differences found in the basal levels of GADD45 were, however, maintained after induction.



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  		Fig. 4. Northern blot analysis in A2780/pCDNA3, A2780/p73.4, and A2780/p73.5 cells. RNA was extracted from untreated cells or 24 h after treatment with DDP (right panel) or UV (left panel) at their respective IC50s.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
In the present study, overexpression of p73{alpha} in a human ovarian cancer cell line resulted in marked up-regulation of genes encoding for DNA repair proteins, thus modifying the ability of cells to repair DNA damage and to become less susceptible to DNA-damaging agents.

The approach used to investigate the changes in gene expression related to p73{alpha} overexpression was to assess a large number of genes by microarray technology. Although several other genes appeared to be affected by p73{alpha} overexpression, we focused subsequent studies on DNA repair genes, which showed in fact the most striking differences. Because the genes encoding for the enzymes involved in NER were consistently up-regulated we examined two DNA-damaging agents, DDP and UV radiation, for which there is convincing evidence that NER plays a crucial role in repairing their cytotoxic DNA lesions (19, 20, 21) .

To our knowledge, this is the first study analyzing the consequences of p73 overexpression on gene expression and response to DNA-damaging agents. The product of the tumor suppressor gene p53 has been widely reported to affect the sensitivity of different cancer cell lines to anticancer drugs treatment (14 , 17 , 22) . Unlike p53, p73 does not seem to be activated after DNA damage (1 , 3 , 12) . In different tumors, however, levels of p73 were higher than in normal tissues (4 , 9, 10, 11) , and this could be an important determinant of response to treatment with anticancer agents.

The decreased response of p73-overexpressing clones to DNA damage could also be attributable to overexpression of GADD45 gene observed in both p73 overexpressing clones. In fact GADD45 has been reported to participate in DNA repair (23) . GADD45 is a p53-responsive gene whose transcription can also be partially activated by DNA damage through a p53-independent mechanisms (24) . The observed increase in GADD45 levels after treatment with DDP and UV in all of the three cell lines used is likely to reflect both of the mechanisms and is in good agreement with previous results obtained in these clones with waf1/p21 gene (12) . The fact that even after induction by DDP and UV, the levels of GADD45 (as well as those of the other genes tested, i.e., XPG, XPD, and XPB) are higher in the two p73-overexpressing clones further support the idea that these genes play a role in the relative resistance observed in these two clones.

With regard to the MMR status, defects in this system have been associated with resistance to DDP (25) . One would, therefore, have expected, from the increase in expression of MMR genes in p73-overexpressing clones, similar or increased DDP activity in these clones. However, the NER status has a much greater effect than MMR on the activity of DDP (20 , 25) . The increase in the levels of MMR genes should have more effect on the activity of methylating agents and, in fact, MNNG was less active in the two p73-overexpressing clones. It has to be noted, however, that both of the clones showed an increased level also of MGMT, a repair enzyme known to strongly affect methylating agents activity.

The fact that a compound not directly interacting with DNA and, therefore, not substrate for NER or MMR systems such as the topoisomerase I inhibitor topotecan showed a similar activity in clones and parental cells, indicates that the two p73-overexpressing clones do not present an intrinsic resistance to drug treatment.

One of the two p73-overexpressing clones (A2780/p73.5) showed a slightly higher degree of resistance to DDP than the other (A2780/p73.4). Because treatment with UV or with another alkylating agent such as MNNG did not result in such a difference, additional mechanisms of DDP resistance could be present in clone A2780/p73.5. Analysis of the expression of genes present in the filters that we used did not reveal any obvious difference in the expression of genes reported to play a critical role in DDP resistance (such as glutathione-S-transferase) between the two clones. It could be that other genes that were not present in these filters show a different pattern of expression, and this is currently under investigation.

The evidence reported here, correlating the cytotoxic activity of drugs with a comprehensive analysis of gene expression, indicate that this could be a useful tool to assess how different genes influence the activity of anticancer agents. At present, we do not know whether p73 overexpression directly accounts for the increase in the expression of genes involved in repair or whether this is a result of cell adaptation to high p73 levels. Similarly it would be interesting to check whether the differences in the expression of genes controlling cell-cell interactions between the two clones predict differences in the behavior of these cells in vivo.

In conclusion, overexpression of p73{alpha} in a human ovarian cancer cell line expressing a wild-type p53 results in resistance to DNA-damaging agents such as DDP, and UV. Although these findings have been thus far obtained in one cell line only, and therefore have to be considered with caution, if confirmed and extended to other cellular systems, they may have important implications because the levels of p73 have been found to be higher in many human tumors than in normal tissues (4 , 9, 10, 11) .


   ACKNOWLEDGMENTS
 
We gratefully acknowledge the generous contribution of the Italian Association for Cancer Research.


   FOOTNOTES
 
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.

1 F. V. is a visiting scientist from Institute of Cytology (Russian Academy of Sciences), St. Petersburg, Russia. S. M. is recipient of a fellowship from the Italian Foundation for Cancer Research (F.I.R.C.). Back

2 F. V. and S. M. contributed equally to this work. Back

3 To whom requests for reprints should be addressed, at Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri," via Eritrea 62, 20157 Milan, Italy. Fax: 39-02-3546277; E-mail: broggini{at}marionegri.it Back

4 The abbreviations used are: DDP, cis-dichlorodiammine platinum; IC50, concentrations inhibiting colony formation by 50%; SSC, 150 mM NaCl-15 mM sodium citrate; DNA-PK, DNA-dependent protein kinase; NER, nucleotide excision repair; ATM, ataxia telengectasia mutated; MMR, mismatch repair; MNNG, methyl-nitro-nitroso-guanidine; MGMT, O6-alkylguanine-DNA-alkyltransferase; RT-PCR, reverse transcription-PCR. Back

5 Internet address: ftp://ftp.marionegri.it/download/microarray. Back

Received 3/31/00. Accepted 12/13/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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M. D'Incalci, E. Erba, G. Damia, E. Galliera, L. Carrassa, S. Marchini, R. Mantovani, G. Tognon, R. Fruscio, J. Jimeno, et al.
Unique Features of the Mode of Action of ET-743
Oncologist, June 1, 2002; 7(3): 210 - 216.
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 MutagenesisHome page
M. L. Smith and Y. R. Seo
p53 regulation of DNA excision repair pathways
Mutagenesis, March 1, 2002; 17(2): 149 - 156.
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 JDRHome page
R. Todd and D.T.W. Wong
DNA Hybridization Arrays for Gene Expression Analysis of Human Oral Cancer
Journal of Dental Research, February 1, 2002; 81(2): 89 - 97.
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 Cell Growth Differ.Home page
M. S. Irwin and W. G. Kaelin
p53 Family Update: p73 and p63 Develop Their Own Identities
Cell Growth Differ., July 1, 2001; 12(7): 337 - 349.
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