Opposing roles of ICAT and Wnt/β-catenin signaling in NSC67657-induced monocytic differentiation

Abstract

NSC67657 is a new steroid drug that induces monocytic differentiation of acute myeloid leukemia cells. Here, we demonstrate that NSC67657 has opposing effects on expression of downstream targets of inhibitor of β-catenin and TCF (ICAT) and Wnt signaling in HL60 cells. ICAT binds to β-catenin, and this interaction is further increased in NSC67657-differentiated cells. ICAT overexpression decreases expression of Wnt downstream targets and increases sensitivity of HL60 cells to NSC67657, while ICAT silencing increases Wnt signaling and delays the NSC67657-induced cell differentiation. In addition, pharmacological inhibition of Wnt/β-catenin signaling increases the NSC67657-induced cell differentiation, while activation of Wnt/β-catenin signaling inhibits the differentiation, indicating Wnt/β-catenin signaling inhibits NSC67657-induced monocytic differentiation of HL60 cells. Our data demonstrate the opposing roles of ICAT and Wnt signaling in the NSC67657-induced monocytic differentiation, and suggest that ICAT and Wnt signaling may serve as therapeutic targets for leukemia chemotherapy.

Expression level and prognostic potential of beta-catenin–interacting protein in acute myeloid leukemia

“…It is known that ICAT regulates the Wnt/β-catenin signaling pathway by inhibiting the binding of β-catenin to TCF/LEF , thus preventing the activation of genes downstream of Wnt signaling. According to previous studies, [ 21 ] HL60 cells exhibit low levels of ICAT protein expression, which can be significantly upregulated by NSC67657 during the monocyte differentiation of HL60 cells. Furthermore, exogenous injection of ICAT protein can significantly improve HL60 cells’ sensitivity to NSC67657.…”

“…NSC67657 is significantly inhibited if the gene encoding intracellular ICAT is silenced. [ 21 ] It has been suggested in a few studies [ 8 ] that the expression level of intracellular ICAT protein level can interfere with chemotherapy and may represent a tumor suppressor in leukemia cells. Although ICAT is a differential protein expressed specifically during monocyte differentiation in HL60 cells and plays an important role in monocyte differentiation, [ 8 ] its regulatory role may interfere with granulocyte induction chemotherapy.…”

The multiple ways Wnt signaling contributes to acute leukemia pathogenesis

“…This effect seems to be at least partially mediated by the inhibition of Wnt/β‐catenin signaling via ICAT induction, a pathway inhibitor. ICAT up‐regulation, as well as pharmacological inhibition of Wnt signaling (XAV‐939), increased the differentiation of HL‐60 cells into monocytes in the presence of NSC67657 145 . Other drugs that indirectly target the Wnt signaling pathway include enzastaurin (a PKCβ selective inhibitor), tested for BCP‐ALL 146 ; salinomycin, tested for APL 147 ; PKC412 and SKLB‐677 (FLT3 inhibitors) as well as imatinib (c‐KIT inhibitor), tested for AML 102,148 …”