Impact of mutant β-catenin on ABCB1 expression and therapy response in colon cancer cells

Abstract

Background:Colorectal cancers are often chemoresistant toward antitumour drugs that are substrates for ABCB1-mediated multidrug resistance (MDR). Activation of the Wnt/β-catenin pathway is frequently observed in colorectal cancers. This study investigates the impact of activated, gain-of-function β-catenin on the chemoresistant phenotype.Methods:The effect of mutant (mut) β-catenin on ABCB1 expression and promoter activity was examined using HCT116 human colon cancer cells and isogenic sublines harbouring gain-of-function or wild-type β-catenin, and patients' tumours. Chemosensitivity towards 24 anticancer drugs was determined by high throughput screening.Results:Cell lines with mut β-catenin showed high ABCB1 promoter activity and expression. Transfection and siRNA studies demonstrated a dominant role for the mutant allele in activating ABCB1 expression. Patients' primary colon cancer tumours shown to express the same mut β-catenin allele also expressed high ABCB1 levels. However, cell line chemosensitivities towards 24 MDR-related and non-related antitumour drugs did not differ despite different β-catenin genotypes.Conclusion:Although ABCB1 is dominantly regulated by mut β-catenin, this did not lead to drug resistance in the isogenic cell line model studied. In patient samples, the same β-catenin mutation was detected. The functional significance of the mutation for predicting patients' therapy response or for individualisation of chemotherapy regimens remains to be established.

Comparative Study of the Sensitivities of Cancer Cells to Doxorubicin, and Relationships between the Effect of the Drug-Efflux Pump P-gp

“…43,44) In addition, HCT-116 cells express several proteins, including P-gp, MRP, LRP. [45][46][47] Similarly, the expression of ABC transporters including P-gp was detected in B16F10 cells. [48][49][50] Therefore, based on the above information, it can be concluded that in the case of G-II cells, efflux pumps play an active role in mediating their sensitivities to DOX in a drug-concentration dependent manner.…”

miR-140-5p inhibits the proliferation and enhances the efficacy of doxorubicin to breast cancer stem cells by targeting Wnt1

“…For instance, Huang et al demonstrated that the Wnt/β-catenin pathway was involved in the RARγ-induced up-regulation of MDR1 in CRC, and RARγ knockdown would suppress MDR1 expression in CRC cells through the Wnt/β-catenin pathway [31]. Additionally, Stein et al reported that the mutation status of β-catenin could determine the ABCB1 expression in a defined cell line model and in colon cancer specimens [32]. Taken together, we speculate that the main mechanism by which miR-140-5p increases the breast cancer sensitivity to Dox is achieved by reducing the expression of Wnt1/ABCB1 signaling.…”

Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance

“…Both mechanisms can be mediated by the efflux transporters Abcc4 , Abcc5 , and Abcc11 , which are involved in discharging endogenous signaling molecules and nucleoside analogues. It has previously been shown that Wnt/β-catenin directly regulates ABCB1 transporter gene transcription in CML and other malignancies (Corrêa et al, 2012; Stein et al, 2012), and that enforced expression of Irf8 antagonized BCR-ABL and overcame drug resistance (Burchert et al, 2004). It was therefore interesting to see that the leukemic GMP fraction displayed enhanced expression of the ABC superfamily of efflux pumps.…”