Abstract
Among the topoisomerase (topo) II isozymes (alpha and beta), topo IIbeta has been suggested to regulate differentiation. In this study, we examined the role of topo IIbeta in all-trans retinoic acid (ATRA)-induced differentiation of myeloid leukemia cell lines. Inhibition of topo IIbeta activity or downregulation of protein expression enhanced ATRA-induced differentiation/growth arrest and apoptosis. ATRA-induced apoptosis in topo IIbeta-deficient cells involved activation of the caspase cascade and was rescued by ectopic expression of topo IIbeta. Gene expression profiling led to the identification of peroxiredoxin 2 (PRDX2) as a candidate gene that was downregulated in topo IIbeta-deficient cells. Reduced expression of PRDX2 validated at the mRNA and protein level, in topo IIbeta-deficient cells correlated with increased accumulation of reactive oxygen species (ROS) following ATRA-induced differentiation. Overexpression of PRDX2 in topo IIbeta-deficient cells led to reduced accumulation of ROS and partially reversed ATRA-induced apoptosis. These results support a role for topo IIbeta in survival of ATRA-differentiated myeloid leukemia cells. Reduced expression of topo IIbeta induces apoptosis in part by impairing the anti-oxidant capacity of the cell owing to downregulation of PRDX2. Thus, suppression of topo IIbeta and/or PRDX2 levels in myeloid leukemia cells provides a novel approach for improving ATRA-based differentiation therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Apoptosis / physiology
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cell Division / drug effects
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Cell Division / physiology
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DNA Topoisomerases, Type II / genetics
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DNA Topoisomerases, Type II / metabolism*
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Diketopiperazines
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Leukemic
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HL-60 Cells
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Humans
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Leukemia, Myeloid / metabolism*
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Leukemia, Myeloid / pathology
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Leukemia, Myeloid / physiopathology
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Peroxidases / genetics
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Peroxidases / metabolism
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Peroxiredoxins
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Piperazines / pharmacology
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RNA, Messenger / metabolism
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Reactive Oxygen Species / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Topoisomerase II Inhibitors
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Tretinoin / pharmacology*
Substances
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Antineoplastic Agents
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DNA-Binding Proteins
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Diketopiperazines
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Enzyme Inhibitors
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Heat-Shock Proteins
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Piperazines
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RNA, Messenger
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Reactive Oxygen Species
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Topoisomerase II Inhibitors
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4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione
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Tretinoin
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Peroxidases
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PRDX2 protein, human
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Peroxiredoxins
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DNA Topoisomerases, Type II