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The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

Oncogene volume 28, pages 2245–2256 (2009)Cite this article

Abstract

The development of chemoresistance represents a major obstacle in the successful treatment of cancers such as neuroblastoma (NB), a particularly aggressive childhood solid tumour. The mechanisms underlying the chemoresistant phenotype in NB were addressed by gene expression profiling of two doxorubicin (DoxR)-resistant vs sensitive parental cell lines. Not surprisingly, the MDR1 gene was included in the identified upregulated genes, although the highest overexpressed transcript in both cell lines was the frizzled-1 Wnt receptor (FZD1) gene, an essential component of the Wnt/β-catenin pathway. FZD1 upregulation in resistant variants was shown to mediate sustained activation of the Wnt/β-catenin pathway as revealed by nuclear β-catenin translocation and target genes transactivation. Interestingly, specific micro-adapted short hairpin RNA (shRNAmir)-mediated FZD1 silencing induced parallel strong decrease in the expression of MDR1, another β-catenin target gene, revealing a complex, Wnt/β-catenin-mediated implication of FZD1 in chemoresistance. The significant restoration of drug sensitivity in FZD1-silenced cells confirmed the FZD1-associated chemoresistance. RNA samples from 21 patient tumours (diagnosis and postchemotherapy), showed a highly significant FZD1 and/or MDR1 overexpression after treatment, underlining a role for FZD1-mediated Wnt/β-catenin pathway in clinical chemoresistance. Our data represent the first implication of the Wnt/β-catenin pathway in NB chemoresistance and identify potential new targets to treat aggressive and resistant NB.

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References

  • Bafico A, Liu G, Goldin L, Harris V, Aaronson SA . (2004). An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 6: 497–506.

    Article  CAS  PubMed  Google Scholar 

  • Bedrnicek J, Vicha A, Jarosova M, Holzerova M, Cinatl JJ, Michaelis M et al. (2005). Characterization of drug-resistant neuroblastoma cell lines by comparative genomic hybridization. Neoplasma 52: 415–419.

    CAS  PubMed  Google Scholar 

  • Blanc E, Goldschneider D, Ferrandis E, Barrois M, Le RG, Leonce S et al. (2003). MYCN enhances P-gp/MDR1 gene expression in the human metastatic neuroblastoma IGR-N-91 model. Am J Pathol 163: 321–331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brodeur GM . (2003). Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3: 203–216.

    Article  CAS  PubMed  Google Scholar 

  • Clevers H . (2006). Wnt/beta-catenin signaling in development and disease. Cell 127: 469–480.

    Article  CAS  PubMed  Google Scholar 

  • Duhem C, Ries F, Dicato M . (1996). What Does Multidrug Resistance (MDR) Expression Mean in the Clinic? Oncologist 1: 151–158.

    CAS  PubMed  Google Scholar 

  • Eisenmann DM . (2005). Wnt signaling. WormBook. pp 1–17.

  • Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC . (2005). Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308: 1181–1184.

    Article  CAS  PubMed  Google Scholar 

  • Flahaut M, Muhlethaler-Mottet A, Martinet D, Fattet S, Bourloud KB, Auderset K et al. (2006b). Molecular cytogenetic characterization of doxorubicin-resistant neuroblastoma cell lines: evidence that acquired multidrug resistance results from a unique large amplification of the 7q21 region. Genes Chromosomes Cancer 45: 495–508.

    Article  CAS  PubMed  Google Scholar 

  • Gillet JP, Efferth T, Remacle J . (2007). Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochim Biophys Acta 1775: 237–262.

    CAS  PubMed  Google Scholar 

  • Goldstein LJ, Fojo AT, Ueda K, Crist W, Green A, Brodeur G et al. (1990). Expression of the multidrug resistance, MDR1, gene in neuroblastomas. J Clin Oncol 8: 128–136.

    Article  CAS  PubMed  Google Scholar 

  • Gottesman MM, Fojo T, Bates SE . (2002). Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2: 48–58.

    Article  CAS  PubMed  Google Scholar 

  • Gregorieff A, Pinto D, Begthel H, Destree O, Kielman M, Clevers H . (2005). Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129: 626–638.

    Article  CAS  PubMed  Google Scholar 

  • Haber M, Bordow SB, Haber PS, Marshall GM, Stewart BW, Norris MD . (1997). The prognostic value of MDR1 gene expression in primary untreated neuroblastoma. Eur J Cancer 33: 2031–2036.

    Article  CAS  PubMed  Google Scholar 

  • Holcombe RF, Marsh JL, Waterman ML, Lin F, Milovanovic T, Truong T . (2002). Expression of Wnt ligands and Frizzled receptors in colonic mucosa and in colon carcinoma. Mol Pathol 55: 220–226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hopkins-Donaldson S, Bodmer JL, Bourloud KB, Brognara CB, Tschopp J, Gross N . (2000). Loss of caspase-8 expression in highly malignant human neuroblastoma cells correlates with resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 60: 4315–4319.

    CAS  PubMed  Google Scholar 

  • Hopkins-Donaldson S, Yan P, Bourloud KB, Muhlethaler A, Bodmer JL, Gross N . (2002). Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells. Oncogene 21: 6132–6137.

    Article  CAS  PubMed  Google Scholar 

  • Johnsson A, Vallon-Christensson J, Strand C, Litman T, Eriksen J . (2005). Gene expression profiling in chemoresistant variants of three cell lines of different origin. Anticancer Res 25: 2661–2668.

    CAS  PubMed  Google Scholar 

  • Kolligs FT, Nieman MT, Winer I, Hu G, Van MD, Feng Y et al. (2002). ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation. Cancer Cell 1: 145–155.

    Article  CAS  PubMed  Google Scholar 

  • Lastowska M, Cullinane C, Variend S, Cotterill S, Bown N, O′Neill S et al. (2001). Comprehensive genetic and histopathologic study reveals three types of neuroblastoma tumors. J Clin Oncol 19: 3080–3090.

    Article  CAS  PubMed  Google Scholar 

  • Lee HY, Kleber M, Hari L, Brault V, Suter U, Taketo MM et al. (2004). Instructive role of Wnt/beta-catenin in sensory fate specification in neural crest stem cells. Science 303: 1020–1023.

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Mazanek P, Dam V, Wang Q, Zhao H, Guo R et al. (2008). Deregulated Wnt/beta-catenin program in high-risk neuroblastomas without MYCN amplification. Oncogene 27: 1478–1488.

    Article  CAS  PubMed  Google Scholar 

  • Longo KA, Kennell JA, Ochocinska MJ, Ross SE, Wright WS, MacDougald OA . (2002). Wnt signaling protects 3T3-L1 preadipocytes from apoptosis through induction of insulin-like growth factors. J Biol Chem 277: 38239–38244.

    Article  CAS  PubMed  Google Scholar 

  • Ludwig JA, Szakacs G, Martin SE, Chu BF, Cardarelli C, Sauna ZE et al. (2006). Selective toxicity of NSC73306 in MDR1-positive cells as a new strategy to circumvent multidrug resistance in cancer. Cancer Res 66: 4808–4815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lustig B, Behrens J . (2003). The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol 129: 199–221.

    CAS  PubMed  Google Scholar 

  • Maris JM, Hogarty MD, Bagatell R, Cohn SL . (2007). Neuroblastoma. Lancet 369: 2106–2120.

    Article  CAS  PubMed  Google Scholar 

  • Merle P, Kim M, Herrmann M, Gupte A, Lefrancois L, Califano S et al. (2005). Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma. J Hepatol 43: 854–862.

    Article  CAS  PubMed  Google Scholar 

  • Milovanovic T, Planutis K, Nguyen A, Marsh JL, Lin F, Hope C et al. (2004). Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma. Int J Oncol 25: 1337–1342.

    CAS  PubMed  Google Scholar 

  • Modok S, Mellor HR, Callaghan R . (2006). Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer. Curr Opin Pharmacol 6: 350–354.

    Article  CAS  PubMed  Google Scholar 

  • Muhlethaler-Mottet A, Bourloud KB, Auderset K, Joseph JM, Gross N . (2004). Drug-mediated sensitization to TRAIL-induced apoptosis in caspase-8-complemented neuroblastoma cells proceeds via activation of intrinsic and extrinsic pathways and caspase-dependent cleavage of XIAP, Bcl-xL and RIP. Oncogene 23: 5415–5425.

    Article  PubMed  Google Scholar 

  • Munoz M, Henderson M, Haber M, Norris M . (2007). Role of the MRP1/ABCC1 multidrug transporter protein in cancer. IUBMB Life 59: 752–757.

    Article  CAS  PubMed  Google Scholar 

  • Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH et al. (1996). In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272: 263–267.

    Article  CAS  PubMed  Google Scholar 

  • Norris MD, Bordow SB, Haber PS, Marshall GM, Kavallaris M, Madafiglio J et al. (1997). Evidence that the MYCN oncogene regulates MRP gene expression in neuroblastoma. Eur J Cancer 33: 1911–1916.

    Article  CAS  PubMed  Google Scholar 

  • Polakis P . (2000). Wnt signaling and cancer. Genes Dev 14: 1837–1851.

    CAS  PubMed  Google Scholar 

  • Psarros M, Heber S, Sick M, Thoppae G, Harshman K, Sick B . (2005). RACE: Remote Analysis Computation for gene Expression data. Nucleic Acids Res 33: W638–W643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seeger RC, Rayner SA, Banerjee A, Chung H, Laug WE, Neustein HB et al. (1977). Morphology, growth, chromosomal pattern and fibrinolytic activity of two new human neuroblastoma cell lines. Cancer Res 37: 1364–1371.

    CAS  PubMed  Google Scholar 

  • Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell R et al. (1999). The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 96: 5522–5527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sinner D, Rankin S, Lee M, Zorn AM . (2004). Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes. Development 131: 3069–3080.

    Article  CAS  PubMed  Google Scholar 

  • Smith KJ, Johnson KA, Bryan TM, Hill DE, Markowitz S, Willson JK et al. (1993). The APC gene product in normal and tumor cells. Proc Natl Acad Sci USA 90: 2846–2850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tetsu O, McCormick F . (1999). Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398: 422–426.

    Article  CAS  PubMed  Google Scholar 

  • Ueno K, Hiura M, Suehiro Y, Hazama S, Hirata H, Oka M et al. (2008). Frizzled-7 as a potential therapeutic target in colorectal cancer. Neoplasia 10: 697–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valent A, Benard J, Venuat AM, Silva J, Duverger A, Duarte N et al. (1999). Phenotypic and genotypic diversity of human neuroblastoma studied in three IGR cell line models derived from bone marrow metastases. Cancer Genet Cytogenet 112: 124–129.

    Article  CAS  PubMed  Google Scholar 

  • Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fodde R et al. (1999). Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol 154: 515–523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamada T, Takaoka AS, Naishiro Y, Hayashi R, Maruyama K, Maesawa C et al. (2000). Transactivation of the multidrug resistance 1 gene by T-cell factor 4/beta-catenin complex in early colorectal carcinogenesis. Cancer Res 60: 4761–4766.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M Wicht and N Besuchet Schmutz (Medical Genetic Service, CHUV) for their skillful help. This study was supported by the Schweizer Forschungsstiftung Kind und Krebs, the Swiss National Science foundation and the FORCE foundation.

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Authors and Affiliations

  1. Department of Paediatrics, Paediatric Oncology Research, University Hospital CHUV, Lausanne, Switzerland

    M Flahaut, A Coulon, K A Nardou, A Mühlethaler-Mottet & N Gross

  2. Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA, USA

    R Meier

  3. Department of Paediatrics, University Children Hospital, Zürich, Switzerland

    F K Niggli

  4. Medical Genetic Service, University Hospital CHUV, Lausanne, Switzerland

    D Martinet & J S Beckmann

  5. Department of Paediatrics, Paediatric Surgery, University Hospital CHUV, Lausanne, Switzerland

    J-M Joseph

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  1. M Flahaut
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Correspondence to M Flahaut.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Flahaut, M., Meier, R., Coulon, A. et al. The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway. Oncogene 28, 2245–2256 (2009). https://doi.org/10.1038/onc.2009.80

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