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

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/b-catenin pathway. FZD1 upregulation in resistant variants was shown to mediate sustained activation of the Wnt/b-catenin pathway as revealed by nuclear b-catenin translocation and target genes transactivation. Interestingly, specific microadapted short hairpin RNA (shRNAmir)-mediated FZD1 silencing induced parallel strong decrease in the expression of MDR1, another b-catenin target gene, revealing a complex, Wnt/b-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/b-catenin pathway in clinical chemoresistance. Our data represent the first implication of the Wnt/b-catenin pathway in NB chemoresistance and identify potential new targets to treat aggressive and resistant NB.

The Cross-Talk between Canonical and Non-Canonical Wnt-Dependent Pathways Regulates P-Glycoprotein Expression in Human Blood–Brain Barrier Cells

“…33 The downregulation of the canonical Wnt/GSK3/b-catenin pathway is known to reduce the Pgp expression and to induce chemosensitization in colon 34 and glioblastoma 17 tumor stem cells, neuroblastoma, 35 chronic myeloid leukemia, 36 and cholangiocarcinoma. 37 Also, the inhibition of the non-canonical Wnt3/ RhoA/RhoAK pathway chemosensitizes multiple myeloma cells to doxorubicin.…”

The NBPF Gene Family

“…Gene expression profiling of two doxorubicin-resistant neuroblastoma cell lines identified the frizzled1 Wnt receptor (FZD1) gene as the most strongly overexpressed transcript in both cell lines in comparison with their sensitive parental cell lines. FZD1 silencing resulted in significant restoration of drug sensitivity and induced a parallel strong decrease in the expression of MDR1 (Flahaut et al, 2009), another β-catenin target gene frequently associated with the resistance of neuroblastoma tumours to chemotherapeutic drugs (Haber et al, 1997). Moreover, FZD1 and/or MDR1 expression was significantly enhanced in the group of relapsed patients after chemotherapy, whereas no significant increase in expression was measured in the group of non-relapsed patients (Flahaut et al, 2009).…”

“…Another study implicated the Wnt-β-catenin pathway in neuroblastoma chemoresistance (Flahaut et al, 2009). Gene expression profiling of two doxorubicin-resistant neuroblastoma cell lines identified the frizzled1 Wnt receptor (FZD1) gene as the most strongly overexpressed transcript in both cell lines in comparison with their sensitive parental cell lines.…”

“…FZD1 silencing resulted in significant restoration of drug sensitivity and induced a parallel strong decrease in the expression of MDR1 (Flahaut et al, 2009), another β-catenin target gene frequently associated with the resistance of neuroblastoma tumours to chemotherapeutic drugs (Haber et al, 1997). Moreover, FZD1 and/or MDR1 expression was significantly enhanced in the group of relapsed patients after chemotherapy, whereas no significant increase in expression was measured in the group of non-relapsed patients (Flahaut et al, 2009). These data indicate that Wnt signalling is important in neuroblastoma tumourigenesis and chemoresistance (overview in Table 1).…”

Exposure of neuroblastoma cell lines to imatinib results in the upregulation of the CDK inhibitor p27KIP1 as a consequence of c-Abl inhibition

“…The expression by neuroblastoma cells of drug efflux transporters of the ABC transporter family such as MDR1 [44] and MRP1 [45] raises the possibility that drug efflux is a major determinant of the reduced sensitivity of neuroblastoma cells to imatinib. However, when evaluating this possibility the following points should be considered.…”