Among the topoisomerase (topo) II isozymes (α and β), topo IIβ has been suggested to regulate differentiation. In this study, we examined the role of topo IIβ in all-trans retinoic acid (ATRA)-induced differentiation of myeloid leukemia cell lines. Inhibition of topo IIβ activity or downregulation of protein expression enhanced ATRA-induced differentiation/growth arrest and apoptosis. ATRA-induced apoptosis in topo IIβ-deficient cells involved activation of the caspase cascade and was rescued by ectopic expression of topo IIβ. Gene expression profiling led to the identification of peroxiredoxin 2 (PRDX2) as a candidate gene that was downregulated in topo IIβ-deficient cells. Reduced expression of PRDX2 validated at the mRNA and protein level, in topo IIβ-deficient cells correlated with increased accumulation of reactive oxygen species (ROS) following ATRA-induced differentiation. Overexpression of PRDX2 in topo IIβ-deficient cells led to reduced accumulation of ROS and partially reversed ATRA-induced apoptosis. These results support a role for topo IIβ in survival of ATRA-differentiated myeloid leukemia cells. Reduced expression of topo IIβ induces apoptosis in part by impairing the anti-oxidant capacity of the cell owing to downregulation of PRDX2. Thus, suppression of topo IIβ and/or PRDX2 levels in myeloid leukemia cells provides a novel approach for improving ATRA-based differentiation therapy.
ASJC Scopus subject areas
- Cancer Research