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

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 β-catenin, in other types of cancer. In this study, we investigated the involvement of the Wnt/β-catenin pathway in the regulation of ABCB1 transcription in CML, as the basal promoter of ABCB1 has several β-catenin binding sites. β-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 β-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 β-catenin levels compared to its parental cell line. Wnt1 and β-catenin depletion and overexpression of nuclear β-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/β-catenin pathway regulates ABCB1 in CML.

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.…”

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

“…Interestingly, it has recently been shown that TCF/LEF dependent signaling activates the ABCB1 promoter indicating that beta-catenin dependent Wnt signaling [19] is involved in ABCB1 expression [20] and therefore potentially in chemoresistance [21,22]. The highly complex and evolutionarily conserved Wnt signaling pathway controls many developmental and tissue maintenance events via the canonical or beta-catenin dependent, and two non-canonical pathways [19].…”

Silencing clusterin gene transcription on effects of multidrug resistance reversing of human hepatoma HepG2/ADM cells

“…Recent studies came up with the conjecture that Wnt/β-catenin was the key gene towards the formation of MDR [30]. Researchers found there were some specific Tcf4/LEF (T-cell factor 4/lymphoid enhancer factor) binding motifs in the promoter of the ABC family; MDR1 was supposed to be a direct target gene of the β-catenin/Tcf4 transcriptional complex.…”