<p>γ-Catenin Overexpression in AML Patients May Promote Tumor Cell Survival via Activation of the Wnt/β-Catenin Axis</p>

Abstract

Background: Canonical Wnt/β-catenin signaling is frequently dysregulated in acute myeloid leukemia (AML) and has been implicated in leukemogenesis. γ-catenin was previously demonstrated to be associated with the nuclear localization of β-catenin, the central mediator, and to exert oncogenic effects in AML; however, the underlying mechanisms remain unclear. Our study aimed to investigate the expression characteristics of γ-catenin in AML patients, explore the mechanisms by which γ-catenin regulates β-catenin, and discuss the feasibility of targeting γ-catenin for AML treatment. Methods: The mRNA expression levels of γ-catenin in AML patients were measured by qRT-PCR. Cell proliferation was examined via Cell Counting Kit-8 (CCK-8) assays. The expression levels of related proteins were measured via Western blotting. Specific siRNA was used to modulate the expression level of the γ-catenin gene. Apoptosis and cell cycle distribution were quantified by flow cytometry. The subcellular localization of γ-catenin and β-catenin was examined via immunofluorescence with a confocal laser scanning microscope. Results: Overexpression of γ-catenin was frequently observed in AML and correlated with poor prognosis. Consistent with this finding, suppression of γ-catenin in the AML cell line THP-1 induced growth inhibition, promoted apoptosis and blocked β-catenin nuclear translocation. Interestingly, γ-catenin knockdown sensitized THP-1 cells to cytotoxic chemotherapeutic agents such as cytarabine and homoharringtonine and further inhibited β-catenin nuclear localization. Moreover, our data implied the relationship between γ-catenin and GSK3β (whose effect on β-catenin is mediated by its own phosphorylation), which may be the principal mechanism underlying the anti-AML effect of γ-catenin inhibition. Conclusion: Taken together, our results revealed a potential role of γ-catenin in AML pathogenesis-mainly through the inhibition of GSK3β-mediated nuclear localization of β-catenin-and indicate that targeting γ-catenin might offer new AML treatments.

The multiple ways Wnt signaling contributes to acute leukemia pathogenesis

“…γ‐Catenin induction led to the activation of TCF‐ and LEF‐target genes, such as MYC and CCND1 ( cyclin D1 ), and it was also associated with β‐catenin stabilization and nuclear localization in leukemic cells 61 . Other studies have corroborated the role of γ‐catenin overexpression in AML pathogenesis 68‐70 . Fusion proteins can also act in Wnt signaling antagonists.…”

“…61 Other studies have corroborated the role of -catenin overexpression in AML pathogenesis. [68][69][70] Fusion proteins can also act in Wnt signaling antagonists. RUNX1-RUNXT1 specifically binds to the SFRP1 promoter, repressing its transcription.…”

Ileal proteomic changes associated with IL-25-mediated resistance against intestinal trematode infections

“…Resistance [25]. Activation of this pathway is essential for the maintenance of the intestinal homeostasis since it plays an essential role in regulating cell proliferation, survival, and differentiation facilitating epithelial healing after disruption [26]. The central mediator of Wnt signaling is β-catenin.…”

Ileal proteomic changes associated with IL-25-mediated resistance against intestinal trematode infections

“…Plakoglobin participates in the canonical pathway of Wnt/β-catenin. Elevated levels of plakoglin promote the stabilization and nuclear localization of β-catenin enhancing the activation of Wnt/β-catenin signaling, and activation of this pathway is essential for the maintenance of intestinal homeostasis [25,26]. Wnt signaling activation is dependent on the nuclear translocation of β-catenin.…”