Article: article from journal or magazin.
The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/beta-catenin pathway.
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/beta-catenin pathway. FZD1 upregulation in resistant variants was shown to mediate sustained activation of the Wnt/beta-catenin pathway as revealed by nuclear beta-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 beta-catenin target gene, revealing a complex, Wnt/beta-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/beta-catenin pathway in clinical chemoresistance. Our data represent the first implication of the Wnt/beta-catenin pathway in NB chemoresistance and identify potential new targets to treat aggressive and resistant NB.
Active Transport, Cell Nucleus/drug effects, Blotting, Western, Caspases/metabolism, Cell Line, Cell Line, Tumor, Cell Nucleus/metabolism, Cell Survival/drug effects, Doxorubicin/pharmacology, Drug Resistance, Neoplasm/genetics, Female, Fluorescent Antibody Technique, Frizzled Receptors/genetics, Frizzled Receptors/metabolism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic/drug effects, Humans, In Situ Hybridization, Fluorescence, Male, Neuroblastoma/drug therapy, Neuroblastoma/genetics, Oligonucleotide Array Sequence Analysis, P-Glycoprotein/genetics, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction/drug effects, Signal Transduction/genetics, Wnt Proteins/genetics, Wnt Proteins/metabolism, beta Catenin/genetics, beta Catenin/metabolism
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