ZNF217 confers resistance to the pro-apoptotic signals of paclitaxel and aberrant expression of Aurora-A in breast cancer cells
- Aurélie Thollet†1, 2, 3, 4,
- Julie A Vendrell†1, 2, 3, 4,
- Léa Payen1, 2, 3, 4,
- Sandra E Ghayad1, 2, 3, 4,
- Sabrina Ben Larbi1, 2,
- Evelyne Grisard1, 2, 3, 4,
- Colin Collins5,
- Marie Villedieu1, 2, 3, 4 and
- Pascale A Cohen1, 2, 3, 4Email author
© Thollet et al; licensee BioMed Central Ltd. 2010
Received: 10 April 2010
Accepted: 8 November 2010
Published: 8 November 2010
ZNF217 is a candidate oncogene located at 20q13, a chromosomal region frequently amplified in breast cancers. The precise mechanisms involved in ZNF217 pro-survival function are currently unknown, and utmost importance is given to deciphering the role of ZNF217 in cancer therapy response.
We provide evidence that stable overexpression of ZNF217 in MDA-MB-231 breast cancer cells conferred resistance to paclitaxel, stimulated cell proliferation in vitro associated with aberrant expression of several cyclins, and increased tumor growth in mouse xenograft models. Conversely, siRNA-mediated silencing of ZNF217 expression in MCF7 breast cancer cells, which possess high endogenous levels of ZNF217, led to decreased cell proliferation and increased sensitivity to paclitaxel. The paclitaxel resistance developed by ZNF217-overexpressing MDA-MB-231 cells was not mediated by the ABCB1/PgP transporter. However, ZNF217 was able to counteract the apoptotic signals mediated by paclitaxel as a consequence of alterations in the intrinsic apoptotic pathway through constitutive deregulation of the balance of Bcl-2 family proteins. Interestingly, ZNF217 expression levels were correlated with the oncogenic kinase Aurora-A expression levels, as ZNF217 overexpression led to increased expression of the Aurora-A protein, whereas ZNF217 silencing was associated with low Aurora-A expression levels. We showed that a potent Aurora-A kinase inhibitor was able to reverse paclitaxel resistance in the ZNF217-overexpressing cells.
Altogether, these data suggest that ZNF217 might play an important role in breast neoplastic progression and chemoresistance, and that Aurora-A might be involved in ZNF217-mediated effects.
In breast cancer, the 20q13 region is amplified in up to 29% of tumors and is associated with early stage, aggressive phenotype and poor clinical prognosis . A number of genes located on chromosome 20q13, such as AURKA/STK15, EEF1A2 and ZNF217, appear as possible oncogenic targets of amplification. ZNF217 amplification correlates with shorter patient survival in breast  and in ovarian cancers . The first direct evidence for a potentially oncogenic function of ZNF217 was the demonstration that the transduction of finite life-span human mammary epithelial cells with ZNF217 could give rise to immortalized cells with increased telomerase activity and stabilized telomere length . It has been hypothesized that the selective amplification of ZNF217 allows cancer cells to overcome senescence and become immortal, a requirement likely essential for cancer development . In support of this original study, ZNF217 has also recently been shown to immortalize ovarian cells .
ZNF217 is a Krüppel-like zinc finger protein that localizes to the nucleus  and interacts with co-repressors and histone modifying proteins [11–13], suggesting that ZNF217 may be part of a transcriptional repressor complex. ZNF217 promotes cell viability in HeLa cells by interfering with the apoptotic pathway and attenuates apoptotic signals resulting from doxorubicin-induced DNA damage or from functionally compromised telomeres . Silencing ZNF217 in ovarian cells suppresses the formation of cell colonies and invasion . Finally, activation of the Akt pathway  and overexpression of the oncogenic translation elongation factor eEF1A2  have been proposed to mediate ZNF217 tumorigenic functions, but the precise molecular mechanisms involved in ZNF217 pro-survival function are currently unknown.
This study aimed to decipher the contribution of ZNF217 in cancer therapy response and to determine whether ZNF217 is able to counteract apoptotic signals other than those induced by DNA damage stimuli. Taxanes are microtubule-stabilizing agents that, by interfering with spindle microtubule dynamics, cause cell cycle arrest and apoptosis. While paclitaxel is recognized as an extremely active chemotherapeutic agent in the treatment of early-stage or metastatic breast cancers, resistance to paclitaxel has become a major concern . In this study, we investigated the functional consequences of aberrant ZNF217 expression on breast cancer cell behavior. We found that ZNF217 confers a highly proliferative and paclitaxel-resistant phenotype to MDA-MB-231 breast cancer cells. To decipher the molecular mechanisms likely responsible for such phenotype, we investigated the possible involvement of the ABCB1/Pgp transporter, of the intrinsic apoptotic pathway and of the oncogenic kinase Aurora-A.
Establishment of stable ZNF217 transfectants of breast cancer cells
Constitutive expression of ZNF217 in MDA-MB-231 breast cancer cells promotes cell proliferation in vitro and tumor growth in vivo
ZNF217 overexpression confers paclitaxel resistance in MDA-MB-231 cells
ABCB1/PgP transporter is not involved in the paclitaxel resistance developed by ZNF217-overexpressing cells
Paclitaxel-induced apoptotic activity is altered in ZNF217-overexpressing MDA-MB-231 cells
Acquired resistance to paclitaxel in ZNF217-overexpressing cells is mediated by alterations of proteins of the Bcl-2 family implicated in the mitochondrial apoptosis pathway
Increased protein expression of the Aurora kinase A/AURKA/STK15 is correlated with constitutive expression of ZNF217 and ZNF217-mediated paclitaxel resistance is reversed in the presence of an Aurora-A inhibitor
With the aim to decipher whether Aurora-A is involved in the paclitaxel resistance developed by the ZNF217-overexpressing cells, we then sought to investigate the impact of an Aurora-A kinase inhibitor on paclitaxel response. The Aurora kinase inhibitor III is a compound known to act as an ATP-competitive and potent inhibitor of Aurora-A (Merck). This inhibitor (5 μM) exerted a weak and similar inhibitory effect (~10%) on viability of both MDA-MB-231/pcDNA6 and ZNF217-1 cells (Figure 9D). In control MDA-MB-231/pcDNA6 cells, combining 5 μM Aurora-A kinase inhibitor with paclitaxel led to an additive inhibitory effect of the two molecules on cell viability (51.5% inhibition under paclitaxel exposure and 63.6% inhibition when combining the Aurora-A kinase inhibitor with paclitaxel). Strikingly, in ZNF217-1 cells, combining 5 μM Aurora-A kinase inhibitor with paclitaxel potentialized paclitaxel cytotoxic effect (Figure 9D, 57% of inhibition of cell viability in Aurora-A kinase inhibitor- and paclitaxel-treated ZNF217-1 cells compared to 24% inhibition of cell viability in paclitaxel-treated ZNF217-1 cells, P < 0.001), and induced a pharmacological response close to that of control paclitaxel-treated MDA-MB-231/pcDNA6 cells. We next investigated the impact of the Aurora-A kinase inhibitor on paclitaxel response in MCF7 cells transfected with either a ZNF217- targeted siRNA or scrambled RNA (Figure 9E). In MCF7 cells transiently transfected with scrambled control RNA (i.e. still possessing high endogenous levels of ZNF217), combining the Aurora-A kinase inhibitor with paclitaxel led to an additive inhibitory effect on cell viability, as observed in ZNF217-overexpressing MDA-MB-231 cells (Figure 9D). More interestingly, combining paclitaxel with the Aurora-A inhibitor in MCF7 cells transiently transfected with a ZNF217- targeted siRNA induced no significant alteration of cell viability (as observed in the control MDA-MB-231/pcDNA6 cells that possess low endogenous levels of ZNF217, Figure 9D). Taken together, these data strongly suggest that the impact of the Aurora-A inhibitor on paclitaxel response is clearly associated with ZNF217 expression levels. Therefore Aurora-A is certainly part of the mechanism by which ZNF217 controls resistance to paclitaxel, and the use of a potent Aurora-A inhibitor could be sufficient to reverse ZNF217-mediated paclitaxel resistance in MDA-MB-231 breast cancer cells.
It has been shown that ZNF217 is able to immortalize human mammary epithelial cells, to overcome senescence and to attenuate apoptotic signals emanating from DNA damage after doxorubicin exposure or from functionally compromised telomeres [7, 14]. The precise mechanisms involved in ZNF217 pro-survival function are currently unknown, and it is thus of utmost importance to decipher the role of ZNF217 in response to cancer therapy.
In this study, we provide evidence that ectopic expression of ZNF217 in MDA-MB-231 breast cancer cells is associated with a highly proliferative phenotype, as constitutive expression of ZNF217 stimulates breast cancer cell proliferation in vitro and tumor growth in vivo in association with aberrant expression of several cyclins. We have also found that high expression levels of ZNF217 in MDA-MB-231 breast cancer cells promote strong resistance (~10-fold) to the microtubule-stabilizing molecule paclitaxel, while no resistance to the nucleoside analogue gemcitabine is concomitantly developed. In accordance with the previous observation that overexpression of ZNF217 decreases doxorubicin-induced cell death in cervical (HeLa) and breast (HBL100) cancer cell lines , the two ZNF217-overexpressing MDA-MB-231 cell lines studied also displayed a ~2.3-fold relative resistance to the topoisomerase inhibitor doxorubicin (data not shown). Our data suggest, firstly, that the chemoresistance mediated by ZNF217 is drug-specific and, secondly, that the molecular mechanisms involved in paclitaxel response are probably more sensitive to the ZNF217-mediated protective action than those involved in response to doxorubicin.
After pointing out that the ABCB1 transporter, known to be involved in taxane and doxorubicin transport, is not responsible for the resistant phenotype developed by ZNF217-overexpressing cells, we aimed to determine which molecular mechanisms are involved in the ZNF217-mediated phenotype. A critical determinant in cellular responses to cytotoxic drugs is the ease with which tumor cells undergo apoptosis . The two major apoptotic pathways rely on either signals transduced through death receptors or signals from mitochondria. Both pathways are involved in the activation of a cascade of caspases, and caspase 3 is a major executioner caspase that cleaves substrates such as PARP, resulting in caspase-dependent apoptosis . In this study, we found that ZNF217 attenuates the apoptotic signals induced by paclitaxel, in association with decreased caspase 3 activity and PARP cleavage. More interestingly, ZNF217-mediated protective effects were associated with alterations in the intrinsic mitochondrial apoptosis pathway, as demonstrated by the deregulation of the balance between pro- and anti-apoptotic members of the Bcl-2 family. Indeed, in both ZNF217-1 and ZNF217-2 cells, high constitutive expression levels of the anti-apoptotic proteins Bcl-2 and Bcl-xL and low constitutive expression levels of the pro-apoptotic proteins Bad, Bax and Bak were detected. Since ectopic overexpression of Bcl-2 or Bcl-xL is necessary to confer resistance to paclitaxel-induced apoptosis  and ectopic overexpression of Bad or Bax have been shown to enhance paclitaxel-induced apoptosis , our data strongly suggest that acquisition of aberrant expression of several members of the Bcl-2 family may be part of the mechanisms developed by ZNF217-1 and ZNF217-2 cells to counteract paclitaxel-induced apoptotic signals.
The p53 pathway has been suggested to be involved in ZNF217 functions , but the ZNF217-driven survival phenotype observed in this study is p53-independent, given that MDA-MB-231 cells possess a non functional mutated p53.
Aurora-A, a serine/threonine kinase located at the centrosome, is overexpressed in 10-60% of breast cancers , functions as a pro-survival protein that promotes tumor cell proliferation, counteracts apoptosis and induces drug resistance in tumor cells [29, 34]. Indeed, Aurora-A overexpression has been associated in cancer cells with spindle checkpoint dysfunction, increased resistance to paclitaxel and docetaxel [28, 29], increased expression of Bcl-2  or of Bcl-xL. Conversely, Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells . In this study, we show for the first time that ZNF217 modulates Aurora-A expression, probably at a post-transcriptional level. Post-transcriptional mechanisms such as phosphorylation-dephosphorylation events  or ubiquitin-dependent proteolysis [38, 39] have been shown to regulate the protein levels of Aurora-A and to play an important role in the functions of this protein [40–42]. Thus ZNF217 may modulate Aurora-A protein turn-over (synthesis or degradation) by still unknown mechanisms. We also newly demonstrated that treatment with a potent Aurora-A kinase inhibitor is able to reverse paclitaxel resistance in ZNF217-overexpressing breast cancer cells. Altogether, these data strongly suggest that the oncogenic Aurora-A kinase could represent a key actor of ZNF217-mediated effects. Finally, as observed for most of kinase inhibitors, the Aurora kinase inhibitor III is also able to target (but at higher concentrations) the activities of other kinases (Lck, Bmx, IGF-1R and Syk). Thus, one cannot exclude that these kinases could also be involved in ZNF217-mediating effects.
Since the AURKA gene is located, like the ZNF217 gene, at 20q13, a region frequently amplified in human cancers, our finding is of particular interest for several reasons. Our data suggest that two known oncogenes, ZNF217 and Aurora-A, may cooperate in breast neoplastic progression and chemoresistance, thus revealing a possible mechanism by which ZNF217 exerts its oncogenic and protective effects. The positive control of ZNF217 on Aurora-A could induce a self-reinforcing amplification of the effect of high levels of ZNF217 expression and/or of increased ZNF217 copy number. As 20q13 amplified breast tumors can either display ZNF217 amplification only or both ZNF217 and AURKA amplifications , one of the mechanisms of breast neoplastic progression could involve the cooperation between the two proteins, either through genomic co-amplification or through ZNF217-mediated regulation of Aurora-A protein expression.
This study demonstrates that ZNF217 counteracts apoptotic signals other than those induced by DNA damage stimuli , and that the protective effects of ZNF217 are associated with constitutive alterations in the balance of Bcl-2 proteins and with constitutive aberrant overexpression of Aurora-A. Given that ZNF217 amplifications have been detected in 8-29% of breast cancers  and that high ZNF217 expression levels are not necessarily correlated to increased ZNF217 gene copy numbers in breast cancer cells [4, 5, 10], increased protein expression of ZNF217 could represent a new mechanism by which breast cancer cells without ZNF217 gene amplification become resistant to paclitaxel. Most importantly, our data suggest that clinical strategies counteracting ZNF217-mediated effects, either by targeting ZNF217 directly and/or by targeting its possible key-mediators like Aurora-A, would be a valuable approach for the management of breast cancer.
Materials and methods
MCF7 and MDA-MB-231 breast cancer cells were purchased from ATCC and grown according to recommendations in DMEM medium supplemented with 10% fetal bovine serum (Invitrogen, Cergy Pontoise, Paris). The identity of MDA-MB-231 cells was confirmed by genomic DNA sequencing (KRAS and TP53 genes) and that of MCF7 cells by their estrogen receptor and progesterone receptor status.
MDA-MB-231-ZNF217 stable transfectants
The full-length ZNF217 cDNA was obtained by adding the missing cDNA sequence, corresponding to the last 6 C-terminal amino acids of the ZNF217 protein, to the pEGFP-N1-ZNF217 plasmid provided by C. Collins, then subcloned into the pcDNA6/V5-His plasmid (Invitrogen) (pcDNA6/V5-His-ZNF217). MDA-MB-231 breast cancer cells were stably transfected with pcDNA6/V5-His or pcDNA6/V5-His-ZNF217 plasmids, then selected in the presence of 20 μg/ml blasticidin (Invitrogen).
Real-time quantitative PCR (RTQ-PCR)
Total RNA from cell culture was prepared using the RNeasy Mini Kit (Qiagen, Hilden, Germany). One microgram of total RNA was reversed-transcribed, and RTQ-PCR measurements were performed as described previously .
Western-blot analysis was performed as previously described . For each sample, total proteins were quantified using a Bradford protein assay and 50 μg of total protein were separated on SDS/PAGE gels before transferring to a PVDF membrane (Sigma-Aldrich, St Quentin Fallavier, France). ZNF217 antibody was obtained from C. Collins , Cyclin D1, PARP, Bax and Aurora-A antibodies were from Cell Signaling (Beverly, MA, USA), Cyclin E2 and Bcl-xL antibodies from Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA), Bcl-2 antibody from Neomarker (Fremont, CA, USA), Bad antibody from BD Biosciences (Franklin Lakes, NJ, USA), Bak and Cyclin E1 antibodies from Calbiochem (San Diego, CA, USA) and Cyclin A2 and α-tubulin antibodies from Sigma Chemical Co. (St. Louis, MO, USA). All western-blots presented are from one experiment representative of at least two independent experiments and cell lysates, and at least three western-blots. Signals were quantified by pixel densitometry using the VisionWorksLS Analysis Software.
Stealth™ siRNAs (siRNA-A and siRNA-B) targeting ZNF217 and scrambled control RNA (scrambled) were obtained from Invitrogen. Five nanomoles of ZNF217-siRNAs or scrambled were transfected into cell lines with lipofectamine RNAimax (Invitrogen).
Cell proliferation analysis
Cells (4 000 cells per well) were plated onto a 96-well plate. Proliferating cells were analyzed using a Cell Proliferation ELISA 5-bromodeoxyuridine (BrdU) Kit (Roche, Meylan, France) as previously described .
Tumor growth assay
A total of 2×106 MDA-MB-231/pcDNA6 or ZNF217-1 cells were suspended in PBS/matrigel v/v (BD Biosciences) and injected into the mammary fat pad of 4-week-old female Swiss nude (nu/nu) mice (Charles River, L'arbresle, France) (control xenografts n = 6 and ZNF217 xenografts n = 7). Tumors were measured with calipers every 3-4 days. All animal studies were performed in accordance with the European Union guidelines and use committee of Centre Léon Bérard.
Cells (8 000 cells per well) were plated onto a 96-well plate, treated for 4 days with 10-12 to 10-6 M of paclitaxel (Paxene®, Ivax, Miami, USA). Cell viability was then assessed with the CellTiter 96 AQueous One Solution Cell Proliferation assay (Promega, Madison, WI, USA). Cytotoxic experiments were also conducted as described above in the presence of Aurora kinase inhibitor III, a potent inhibitor of Aurora-A (Merck, Nottingham, UK), alone or combined with 2.5 nM paclitaxel.
Flow cytometry analysis of ABCB1 protein expression levels
ABCB1 protein levels were quantified by flow cytometry in ABCB1-positive control K562-R7, MDA-MB-231/pcDNA6, ZNF217-1 and ZNF217-2 cells using the ABCB1-C219 (phycoerythrin PE)-conjugated antibody (Santa Cruz) according to the manufacturer's instructions.
At the end of uptake phase (30 min, 37°C), daunorubicin (17 μM DNR, DaunoXome®, San Dimas, CA, USA) was removed and cells were re-incubated for 1 h in DNR-free medium in the presence or absence of 4 μg/ml cyclosporin A (CSA). After trypsination, DNR fluorescence was monitored with a FACscan flow cytometer (Becton Dickinson, Mountain View, CA, USA) as previously described .
Detection of apoptosis by annexin-V staining
The cells were grown for 3 days and treated or not with 10 nM or 100 nM of paclitaxel. Apoptotic cells were detected using the Annexin-V-FLUOS Staining Kit (Roche). FITC fluorescence was then analyzed in 2×104 cells by a FACscan flow cytometer. The percentage of apoptotic cells was determined by analysis with cellQuest(tm) software (Becton Dickinson).
Caspase 3 activity assay
Briefly, cells were treated or not with 100 nM of paclitaxel for 10 h. Caspase 3 activity was determined using the Caspase-3/CPP32 fluorometric assay kit (Clinisciences, Montrouge, France).
We thank Ms. MD Reynaud for editing the manuscript and Dr I Puisieux for helpful advice concerning mouse xenograft experiments. This work was supported by the Ligue Nationale Contre le Cancer (Comité du Rhône, Comité de la Saône-et-Loire).
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