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The Wnt Receptor FZD1 Mediates Chemoresistance in Neuroblastoma Through Activation of the Wnt/B-Catenin Pathway

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The Wnt Receptor FZD1 Mediates Chemoresistance in Neuroblastoma Through Activation of the Wnt/B-Catenin Pathway Oncogene (2009) 28, 2245–2256 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc ORIGINAL ARTICLE The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/b-catenin pathway M Flahaut1, R Meier2, A Coulon1, KA Nardou1, FK Niggli3, D Martinet4, JS Beckmann4, J-M Joseph5,AMu¨ hlethaler-Mottet1 and N Gross1 1Department of Paediatrics, Paediatric Oncology Research, University Hospital CHUV, Lausanne, Switzerland; 2Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA, USA; 3Department of Paediatrics, University Children Hospital, Zu¨rich, Switzerland; 4Medical Genetic Service, University Hospital CHUV, Lausanne, Switzerland and 5Department of Paediatrics, Paediatric Surgery, University Hospital CHUV, Lausanne, Switzerland The development of chemoresistance represents a major Introduction obstacle in the successful treatment of cancers such as neuroblastoma (NB), a particularly aggressive childhood Drug resistance acquired in the course of therapy is a solid tumour. The mechanisms underlyingthe chemore- major obstacle in the successful treatment of many sistant phenotype in NB were addressed by gene expres- cancers. A promising initial response of the tumour to sion profilingof two doxorubicin (DoxR)-resistant vs chemotherapy by shrinking of the tumour volume is sensitive parental cell lines. Not surprisingly, the MDR1 frequently observed, followed by appearance of multi- gene was included in the identified upregulated genes, drug resistant variants and chemoresistance (Duhem although the highest overexpressed transcript in both cell et al., 1996; Ludwig et al., 2006). The multiple lines was the frizzled-1 Wnt receptor (FZD1) gene, an mechanisms contributing to chemoresistance are only essential component of the Wnt/b-catenin pathway. FZD1 partially elucidated (Gottesman et al., 2002). One of the upregulation in resistant variants was shown to mediate best-studied mechanisms conferring chemoresistance to sustained activation of the Wnt/b-catenin pathway as cancer cells is the increased drug efflux lowering revealed by nuclear b-catenin translocation and target intracellular drug concentration. This drug efflux is genes transactivation. Interestingly, specific micro- partially mediated by cell surface glycoproteins, which adapted short hairpin RNA (shRNAmir)-mediated belong to the family of ATP-binding cassette (ABC) of FZD1 silencinginduced parallel strongdecrease in the multidrug transporters (Gottesman et al., 2002). ABC expression of MDR1, another b-catenin target gene, transporters, such as MDR1 (multidrug resistance gene) revealinga complex, Wnt/ b-catenin-mediated implication and MRP1 (MDR-related protein), are highly expressed of FZD1 in chemoresistance. The significant restoration in many human cancers including neuroblastoma (NB) of drugsensitivity in FZD1-silenced cells confirmed the (Haber et al., 1997; Norris et al., 1997; Blanc et al., 2003; FZD1-associated chemoresistance. RNA samples from 21 Munoz et al., 2007), and they are associated with the patient tumours (diagnosis and postchemotherapy), resistance of these tumours to chemotherapeutic drugs showed a highly significant FZD1 and/or MDR1 (Haber et al., 1997; Norris et al., 1997; Gottesman et al., overexpression after treatment, underlininga role for 2002). FZD1-mediated Wnt/b-catenin pathway in clinical che- NB is the most common extracranial solid tumour moresistance. Our data represent the first implication of in childhood that accounts for 8–10% of cancers the Wnt/b-catenin pathway in NB chemoresistance and and 15% of all cancer-related deaths in childhood identify potential new targets to treat aggressive and (Maris et al., 2007). Despite recent advances in resistant NB. combined therapies, recurrent disease in patients with Oncogene (2009) 28, 2245–2256; doi:10.1038/onc.2009.80; high risk NB remains a major clinical problem due to published online 4 May 2009 treatment failure, which is mainly attributed to the development of chemoresistance during treatment. NB Keywords: neuroblastoma; chemoresistance; FZD1; can be regarded as developmental disease as it originates MDR1; Wnt signalling from primitive cells of the sympathetic nervous system (Brodeur, 2003). During development, the Wnt signalling pathway plays a key role by controlling multiple aspects, such as proliferation, fate, specification, polarity and migration Correspondence: Dr M Flahaut, Paediatric Oncology Research, of cells. Sustained activation of this pathway by Paediatric Department, University Hospital CHUV, CH-1011 mutation is a major factor in oncogenesis in many Lausanne, Switzerland. E-mail: [email protected] cancers (Polakis, 2000; Eisenmann, 2005). Upon Wnt Received 16 December 2008; revised 6 March 2009; accepted 14 March ligand binding to cell surface receptors of the 2009; published online 4 May 2009 Frizzled family (FZD) and coreceptors from the Wnt signalling in chemoresistant NB M Flahaut et al 2246 family of low-density lipoprotein receptor-related Results proteins (LRP-5/6), the intrinsic kinase activity of the adenomatous polyposis coli (APC)/Axin/CK1/GSK3b Identification of differentially expressed genes destruction complex is blocked. This leads to the in chemoresistant cells stabilization and accumulation of cytoplasmic b-cate- The gene expression profile of IGRN-91-R cells was nin, which is subsequently translocated to the nucleus compared with the IGRN-91 parental cell line. The (Lee et al., 2004) and thereby activated. The interaction comparison revealed 16 significantly upregulated genes of b-catenin with the TCF/LEF transcription (>4-fold) in the IGRN-91-R cell line (Table 1). As factors leads to the transcription of Wnt target expected, the MDR1/ABCB1 transcript was highly genes (Eisenmann, 2005). In a majority of tumours, overexpressed in the resistant cell line (27.5-fold aberrant activation of the Wnt/b-catenin is the conse- increase). Interestingly, FZD1 encoding the frizzled 1 quence of APC, Axin or b-catenin gene mutations receptor, a seven transmembrane receptor member of (Lustig and Behrens, 2003). Moreover, it has been the Wnt/b-catenin signalling pathway was found to be shown that overactivation of the Wnt signalling path- the highest upregulated transcript (34.5-fold stimula- way is due to the overexpression of different FZD tion) in resistant cells. Moreover, 12 out of 16 receptors in a variety of cancers (Milovanovic et al., transcripts in the list of upregulated transcripts corre- 2004; Merle et al., 2005; Ueno et al., 2008). In NB, sponded to genes located on the 7q21 region as b-catenin has been shown to be strongly expressed and published earlier (Flahaut et al., 2006b). As the 7q21 aberrantly localized in the nucleus in highly aggressive amplified region also harbours the FZD1 gene, we now NB cells without MYCN amplification, whereas no investigated whether the two MDR1 and FZD1 genes b-catenin-specific mutations were identified (Liu et al., were coamplified. Fluorescent in situ hybridization was 2008). carried out with MDR1-, FZD1- and chromosome 7 To elucidate genes and pathways involved in centromeric-specific probes (labelled green and red for chemoresistance in NB cells, we have further MDR1 and FZD1, respectively) on the resistant IGRN- analysed chemoresistant NB cell lines generated by 91-R and LAN-1-R cells and their corresponding prolonged exposure to doxorubicin (DoxR cells; sensitive counterparts. Figure 1a shows a colocalization Flahaut et al., 2006b). We have recently reported that of strong MDR1 and FZD1 signals detected in some DoxR NB cell lines exhibited overexpression chromosomes of the resistant IGRN-91-R and LAN-1- of the MDR1 gene due to an amplification at the 7q21 R cells. None of the sensitive parental cell lines revealed locus. As the MDR1/P-gp inhibitor verapamil was not this cytogenetic pattern (data not shown). Interestingly, able to restore 100% of cell sensitivity to DoxR, in the resistant LAN-1-R cells, coamplified MDR1/ etoposide or paclitaxel, we postulated that P-glycopro- FZD1 signals were also detected on chromosome 7, tein-mediated drug efflux was not responsible for implying an underlying general mechanism conferring 100% drug resistance (Flahaut et al., 2006b). In drug resistance. However, only a few coamplified genes this study, microarray expression profile analysis of mapping in this amplicon were also found to be resistant variants revealed 7q21 region-related amplifi- upregulated at the mRNA level (data not shown). Thus, cation and overexpression of several genes, including the high level of FZD1 expression likely to be MDR1 and the Wnt receptor FZD1. These genes biologically relevant was further validated by semi- are shown to mediate chemoresistance in DoxR cell quantitative real-time PCR. MDR1/ABCB1 and FZD1 lines and patients, through Wnt/b-catenin pathway transcripts expression levels were measured in the two activation. DoxR cell lines (IGRN-91-R and LAN-1-R) compared Table 1 Affymetrix microarray analysis of significantly upregulated genes in the IGRN-91-R cell line compared with the IGRN-91 cell line Probe set Fold increase Gene Abbreviation Accession no. CHR 204451_at 34.48 Frizzled homologue 1 (Drosophila) FZD1 NM_003505.1 7q21.13 204115_at 31.76 Guanine nucleotide-binding protein 11 GNG11 NM_004126.3 7q21.3 209994_s_at 27.45 ATP-binding cassette, subfamily B, member 1 MDR1/ABCB1 AF016535.1 7q21.12 204688_at 23.88 Sarcoglycan, epsilon SGCE NM_003919.2 7q21.3 202710_at 21.70 BET1 homologue
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