title: Downregulation of topoisomerase IIbeta in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation/growth arrest.
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.
authors.affiliation: Experimental Therapeutics Program, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: K
authors.initials: K
authors.lastname: Chikamori
authors.forename: J E
authors.initials: JE
authors.lastname: Hill
authors.forename: D R
authors.initials: DR
authors.lastname: Grabowski
authors.forename: E
authors.initials: E
authors.lastname: Zarkhin
authors.forename: A G
authors.initials: AG
authors.lastname: Grozav
authors.forename: S A J
authors.initials: SA
authors.lastname: Vaziri
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: A V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: L R
authors.initials: LR
authors.lastname: Rybicki
authors.forename: R M
authors.initials: RM
authors.lastname: Bukowski
authors.forename: A
authors.initials: A
authors.lastname: Yen
authors.forename: M
authors.initials: M
authors.lastname: Tanimoto
authors.forename: M K
authors.initials: MK
authors.lastname: Ganapathi
authors.forename: R
authors.initials: R
authors.lastname: Ganapathi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054659:Diketopiperazines; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010544:Peroxidases / Q000235:genetics / Q000378:metabolism; D054464:Peroxiredoxins; D010879:Piperazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D059005:Topoisomerase II Inhibitors; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D010879:Piperazines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D014212:Tretinoin; D010544:Peroxidases; C086065:PRDX2 protein, human; D054464:Peroxiredoxins; D004250:DNA Topoisomerases, Type II