The interplay of autophagy and β-Catenin signaling regulates differentiation in acute myeloid leukemia

Abstract

The major feature of leukemic cells is an arrest of differentiation accompanied by highly active proliferation. In many subtypes of acute myeloid leukemia, these features are mediated by the aberrant Wnt/β-Catenin pathway. In our study, we established the lectin LecB as inducer of the differentiation of the acute myeloid leukemia cell line THP-1 and used it for the investigation of the involved processes. During differentiation, functional autophagy and low β-Catenin levels were essential. Corresponding to this, a high β-Catenin level stabilized proliferation and inhibited autophagy, resulting in low differentiation ability. Initiated by LecB, β-Catenin was degraded, autophagy became active and differentiation took place within hours. Remarkably, the reduction of β-Catenin sensitized THP-1 cells to the autophagy-stimulating mTOR inhibitors. As downmodulation of E-Cadherin was sufficient to significantly reduce LecB-mediated differentiation, we propose E-Cadherin as a crucial interaction partner in this signaling pathway. Upon LecB treatment, E-Cadherin colocalized with β-Catenin and thereby prevented the induction of β-Catenin target protein expression and proliferation. That way, our study provides for the first time a link between E-Cadherin, the aberrant Wnt/β-Catenin signaling, autophagy and differentiation in acute myeloid leukemia. Importantly, LecB was a valuable tool to elucidate the underlying molecular mechanisms of acute myeloid leukemia pathogenesis and may help to identify novel therapy approaches.

A‐kinase interacting protein 1 might serve as a novel biomarker for worse prognosis through the interaction of chemokine (C‐X‐C motif) ligand 1/chemokine (C‐X‐C motif) ligand 2 in acute myeloid leukemia

“…Another study displays that increased AKIP1 expression is associated with early recurrence and AKIP1 is a potential mediator of tumor metastasis via regulating Wnt/β‐catenin signaling in hepatocellular carcinoma . Furthermore, Wnt/β‐catenin signaling, as an oncogenic signaling in both solid tumors and hematologic malignancies, is reported to be associated with the AML‐related fusion proteins and FLT3‐1TD mutation, which correlated with unfavorable survival profiles in AML patients . Nevertheless, the role of AKIP1 in hematologic malignancies has been rarely investigated.…”

“…7 Furthermore, Wnt/β-catenin signaling, as an oncogenic signaling in both solid tumors and hematologic malignancies, is reported to be associated with the AML-related fusion proteins and FLT3-1TD mutation, which correlated with unfavorable survival profiles in AML patients. 15 Nevertheless, the role of AKIP1 in hematologic malignancies has been rarely investigated. In addition, recent studies illustrate that CXCL1 and CXCL2 are activated by AKIP1 during the oncogenic development, and CXCL1/CXCL2 regulate AML cell migration during the leukemogenesis.…”

Role of autophagy in the regulation of epithelial cell junctions

“…The independent and constitutively active b-catenin blocked autophagy and promoted proliferation. 48 However, treatment with lectin LecB was found to degrade b-catenin, allowing induction of autophagy and suppress deregulated proliferation of leukemia THP-1 cells. 48 Autophagy is also known to contribute to therapyinduced degradation of the PML/RARA oncoprotein, allowing terminal differentiation of immature precursor cells and suppress deregulated proliferation of myeloid cells.…”

“…48 However, treatment with lectin LecB was found to degrade b-catenin, allowing induction of autophagy and suppress deregulated proliferation of leukemia THP-1 cells. 48 Autophagy is also known to contribute to therapyinduced degradation of the PML/RARA oncoprotein, allowing terminal differentiation of immature precursor cells and suppress deregulated proliferation of myeloid cells. 49 Moreover, the reduced levels of b-catenin also sensitized leukemia THP-1 cells to mTOR inhibitors, suggesting a potential solution for the low clinical benefit of mTOR inhibitors in AML patients.…”

Abrus agglutinin stimulates BMP‐2‐dependent differentiation through autophagic degradation of β‐catenin in colon cancer stem cells

“…In a similar vein, an AGG‐induced decrease in β‐catenin content was an autophagy‐dependent degradation, and 3‐MA treatment was associated with a reduction in the decrease of expression of β‐catenin and thus, a reduction in the differentiation potential in HT‐29 colonospheres. Previously, a fucose‐binding lectin LecB has been identified as an effective differentiation‐inducing agent through autophagic degradation of β‐catenin in acute myeloid leukemia …”