Knockdown of the Wnt receptor Frizzled-1 (FZD1) reduces MDR1/P-glycoprotein expression in multidrug resistant leukemic cells and inhibits leukemic cell proliferation

Abstract

Multidrug resistance (MDR) is a major obstacle to leukemia treatment. The Frizzled-1 (FZD1) Wnt receptor is involved in MDR in some solid cancers, but has rarely been reported to act in acute myeloid leukemia (AML). We investigated whether the knockdown of FZD1 affects MDR1 expression and P-glycoprotein (P-gp) function in multidrug resistant leukemic cell lines, as well as FZD1 and MDR1/P-gp expression in leukemic cells taken from patients with AML (n = 112). FZD1 knockdown significantly reduced MDR1 expression through the Wnt/β-catenin pathway, disrupted the P-gp efflux function, induced the recovery of sensitivity to chemotherapeutic agents, and hindered cell proliferation in cell lines. FZD1 expression in leukemic cells was significantly higher in patients experiencing relapse (n = 34) than in those with no relapse (n = 44, P = .003). Leukemic cells unable to achieve complete response (CR) showed an increased expression of MDR1 and P-gp, compared to patients who achieved CR. Obtaining CR in patients with higher FZD1 expression at diagnosis is difficult. Moreover, they tend to present instances of relapse, suggesting that AML cells with increased FZD1 expression are resistant to chemotherapy. We conclude that the activated FZD1 observed in leukemic cells likely confers acquired drug resistance, whereas FZD1 silencing may be more effective in reversing MDR.