γ-Catenin Overexpression in AML Patients May Promote Tumor Cell Survival via Activation of the Wnt/β-Catenin Axis.
ONCOTARGETS AND THERAPY(2020)
Abstract
Background: Canonical Wnt/beta-catenin signaling is frequently dysregulated in acute myeloid leukemia (AML) and has been implicated in leukemogenesis. gamma-catenin was previously demonstrated to be associated with the nuclear localization of beta-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 gamma-catenin in AML patients, explore the mechanisms by which gamma-catenin regulates beta-catenin, and discuss the feasibility of targeting gamma-catenin for AML treatment. Methods: The mRNA expression levels of gamma-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 gamma-catenin gene. Apoptosis and cell cycle distribution were quantified by flow cytometry. The subcellular localization of gamma-catenin and beta-catenin was examined via immunofluorescence with a confocal laser scanning microscope. Results: Overexpression of gamma-catenin was frequently observed in AML and correlated with poor prognosis. Consistent with this finding, suppression of gamma-catenin in the AML cell line THP-1 induced growth inhibition, promoted apoptosis and blocked beta-catenin nuclear translocation. Interestingly, gamma-catenin knockdown sensitized THP-1 cells to cytotoxic chemotherapeutic agents such as cytarabine and homoharringtonine and further inhibited beta-catenin nuclear localization. Moreover, our data implied the relationship between gamma-catenin and GSK3 beta (whose effect on beta-catenin is mediated by its own phosphorylation), which may be the principal mechanism underlying the anti-AML effect of gamma-catenin inhibition. Conclusion: Taken together, our results revealed a potential role of gamma-catenin in AML pathogenesis-mainly through the inhibition of GSK3 beta-mediated nuclear localization of beta-catenin-and indicate that targeting gamma-catenin might offer new AML treatments.
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Key words
acute myeloid leukemia,gamma-catenin,beta-catenin,chemotherapy
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