Combined Application of Salinomycin and ATRA Induces Apoptosis and Differentiation of Acute Myeloid Leukemia Cells by Inhibiting WNT/β-Catenin Pathway

Author(s):

Hui-Min Xi, Hao Lu, Xiang-Qin Weng, Yan Sheng, Jing Wu, Lu Li and Xun Cai*   Pages 1074 - 1084 ( 11 )

Abstract:

<p>Background and Objective: All-trans retinoic acid (ATRA) is only effective in acute promyelocytic leukemia (APL), but not in other subtype of acute myeloid leukemia (AML). Salinomycin targets tumor cells rather than non-tumorigenic cells, and WNT/&#946;-catenin pathway inhibition is one of the mechanisms of its anti-tumor activity. There is a crosstalk between RA and WNT/&#946;-catenin pathway. Here, we investigate the effect of the combination of salinomycin and ATRA (S+RA) in non-APL AML cells. <p> Methods: Apoptosis was evaluated by cell viability and Annexin-V assay. Cell differentiation was analyzed by CD11c expression and morphology. To explore the underlying mechanisms, Western blot analysis and mitochondrial transmembrane potentials (ΔΨm) were used. <p> Results & Discussion: S+RA induced differentiation and apoptosis in AML cell lines and AML primary cells. S+RA inhibited the &#946;-catenin signal pathway as determined by the decreased protein levels of &#946;-catenin, the low-density lipoprotein receptor-related proteins 6 (LRP6), and its downstream proteins such as survivin, c-Myc, caspase-3/7, cdc25A and cyclinD1 and reduced phosphorylation level of GSK3&#946; S9. S+RA also increased the protein levels of CCAAT/enhancer-binding proteins (C/EBPs) and PU.1 and collapsed &#916;&#968;m. The above molecular and cellular changes induced by S+RA were inhibited by &#946;-catenin specific activator and promoted by &#946;-catenin specific inhibitor. <p> Conclusion: S+RA induced differentiation by &#946;-catenin-inhibition-mediated up-regulation of C/EBPs and PU.1 and suppression of c-Myc. S+RA triggered apoptosis through &#946;-catenin-inhibition-regulated ΔΨm collapse and caspase-3/7 activation. Taken together, our findings may provide novel therapeutic strategies for AML patients by targeting the WNT/&#946;-catenin pathway.</p>

Keywords:

All-trans retinoic acid, acute myeloid leukemia, salinomycin, &#946;-catenin, differentiation, apoptosis.

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