Title:Combined Application of Salinomycin and ATRA Induces Apoptosis and Differentiation
of Acute Myeloid Leukemia Cells by Inhibiting WNT/β-Catenin Pathway
Volume: 23
Issue: 9
Author(s): Hui-Min Xi, Hao Lu, Xiang-Qin Weng, Yan Sheng, Jing Wu, Lu Li and Xun Cai*
Affiliation:
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine
at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
Keywords:
All-trans retinoic acid, acute myeloid leukemia, salinomycin, β-catenin, differentiation, apoptosis.
Abstract:
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/β-catenin pathway inhibition is one of the mechanisms of its anti-tumor activity.
There is a crosstalk between RA and WNT/β-catenin pathway. Here, we investigate the effect of the combination of
salinomycin and ATRA (S+RA) in non-APL AML cells.
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.
Results & Discussion: S+RA induced differentiation and apoptosis in AML cell lines and AML primary cells. S+RA
inhibited the β-catenin signal pathway as determined by the decreased protein levels of β-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 GSK3β S9. S+RA also increased the protein levels of
CCAAT/enhancer-binding proteins (C/EBPs) and PU.1 and collapsed Δψm. The above molecular and cellular changes
induced by S+RA were inhibited by β-catenin specific activator and promoted by β-catenin specific inhibitor.
Conclusion: S+RA induced differentiation by β-catenin-inhibition-mediated up-regulation of C/EBPs and PU.1 and
suppression of c-Myc. S+RA triggered apoptosis through β-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/β-catenin pathway.