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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.

SUBMITTER: Wang W

PROVIDER: S-EPMC5642527 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Wang Weijia W Zhang Yan Y Yuan Yong Y Yuan Runqiang R Yang Youye Y Zhang Xiuming X Wen Dongmei D Huang Fuda F Wang Jinshu J

Oncotarget 20170722 41

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 ...[more]

PMID: 29050252

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Project description:Objectives: To investigate the effect of β-catenin interacting protein 1 (ICAT) silence in Wnt signaling pathway and sterol drug NSC67657 induced cell differentiation of HL60 cell. Methods: HL-60 cells were treated with NSC67657, the cell surface antigen CD14 expression was detected by flow cytometry. Lentivirus LV-ICAT-RNAi vector was constructed and infected HL-60 cells. Then the ICAT gene and protein expression were analyzed using real-time qPCR and Western blot technique. Furthermore, Co-immunoprecipitation assay was used to confirm the interaction of β-catenin/ICAT proteins, and Western blot was employed to compare the expressions of Wnt signaling pathway downstream targets Cyclin D1, TCF-1 and c-Jun between Lentivirus LV-ICAT-RNAi vector infected HL-60 (HL-60i) cells and un-infected HL-60 (HL-60v) cells. The cellular differentiation of HL-60i and HL-60v cells treated with NSC67657 for 24 h was evaluated by Wright's staining, transmission electron microscopy and flow cytometry analysis. Results: HL-60 cells could be induced to differentiate into monocytes by 10 μmol/L NSC67657. The CD14 positive cells could reach to (92.30±5.14) % after NSC67657 treatment for 5d. The co- immunoprecipitation assay demonstrated that ICAT protein did interact with β-catenin protein, and the absorbance of protein electrophoresis bands increased in differentiated cells. The expressions of Wnt signaling pathway downstream target proteins in HL-60i cells were higher than that in HL-60v cells when they were treated by 10 μmol/L NSC67657, but lower than NSC67657 untreated cells. CD14 positive HL-60i cells were significantly lower than that of HL-60v cells[ (8.33±3.14) % vs (19.08±4.73) %]when treated with NSC67657, but still higher than that of uninfected and untreated HL60 cells[ (0.60±0.03) %] (F=119.24, P=0.010) . The results of cellular morphology and ultrastructure observation were also in accord with that of cell surface antigen analysis. Conclusions: ICAT does participate in HL-60 cells monocytic differentiation induced by NSC67657, and Wnt/β-catenin signaling pathway might play a bridge role.

Dataset Information

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

Publications

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

Similar Datasets

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