Wnt/β-catenin pathway regulates ABCB1 transcription in chronic myeloid leukemia

被引:93
作者
Correa, Stephany [1 ,2 ]
Binato, Renata [1 ]
Du Rocher, Barbara [1 ]
Castelo-Branco, Morgana T. L. [3 ]
Pizzatti, Luciana [1 ]
Abdelhay, Eliana [1 ,2 ]
机构
[1] INCA, Div Labs CEMO, Rio De Janeiro, Brazil
[2] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21941 Rio De Janeiro, Brazil
[3] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, BR-21941 Rio De Janeiro, Brazil
关键词
CANCER STEM-CELLS; P-GLYCOPROTEIN; BETA-CATENIN; GENE-EXPRESSION; MULTIDRUG-RESISTANCE-1; GENE; MULTIDRUG-RESISTANCE; KINASE INHIBITORS; IMATINIB MESYLATE; BCR; MDR1;
D O I
10.1186/1471-2407-12-303
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 beta-catenin, in other types of cancer. In this study, we investigated the involvement of the Wnt/beta-catenin pathway in the regulation of ABCB1 transcription in CML, as the basal promoter of ABCB1 has several beta-catenin binding sites. beta-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: beta-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 beta-catenin levels compared to its parental cell line. Wnt1 and beta-catenin depletion and overexpression of nuclear beta-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/beta-catenin pathway regulates ABCB1 in CML.
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页数:11
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