Wnt/ß-catenin pathway regulates ABCB1 transcription in chronic myeloid leukemia.
BMC Cancer
; 12: 303, 2012 Jul 23.
Article
en En
| MEDLINE
| ID: mdl-22823957
ABSTRACT
BACKGROUND:
The advanced phases of chronic myeloid leukemia (CML) are known to be more resistant to therapy. This resistance has been associated with the overexpression of ABCB1, which gives rise to the multidrug resistance (MDR) phenomenon. MDR is characterized by resistance to nonrelated drugs, and P-glycoprotein (encoded by ABCB1) has been implicated as the major cause of its emergence. Wnt signaling has been demonstrated to be important in several aspects of CML. Recently, Wnt signaling was linked to ABCB1 regulation through its canonical pathway, which is mediated by ß-catenin, in other types of cancer. In this study, we investigated the involvement of the Wnt/ß-catenin pathway in the regulation of ABCB1 transcription in CML, as the basal promoter of ABCB1 has several ß-catenin binding sites. ß-catenin is the mediator of canonical Wnt signaling, which is important for CML progression.METHODS:
In this work we used the K562 cell line and its derived MDR-resistant cell line Lucena (K562/VCR) as CML study models. Real time PCR (RT-qPCR), electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), flow cytometry (FACS), western blot, immunofluorescence, RNA knockdown (siRNA) and Luciferase reporter approaches were used.RESULTS:
ß-catenin was present in the protein complex on the basal promoter of ABCB1 in both cell lines in vitro, but its binding was more pronounced in the resistant cell line in vivo. Lucena cells also exhibited higher ß-catenin levels compared to its parental cell line. Wnt1 and ß-catenin depletion and overexpression of nuclear ß-catenin, together with TCF binding sites activation demonstrated that ABCB1 is positively regulated by the canonical pathway of Wnt signaling.CONCLUSIONS:
These results suggest, for the first time, that the Wnt/ß-catenin pathway regulates ABCB1 in CML.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Transcripción Genética
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Leucemia Mielógena Crónica BCR-ABL Positiva
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Transducción de Señal
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
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Proteínas Wnt
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Beta Catenina
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2012
Tipo del documento:
Article