NF-kappaB-inhibited acute myeloid leukemia cells are rescued from apoptosis by heme oxygenase-1 induction

Rushworth, Stuart A, Bowles, Kristian M, Raninga, Prahlad and MacEwan, David J (2010) NF-kappaB-inhibited acute myeloid leukemia cells are rescued from apoptosis by heme oxygenase-1 induction. Cancer Research, 70 (7). pp. 2973-2983. ISSN 0008-5472

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Abstract

Despite high basal NF-kappaB activity in acute myeloid leukemia (AML) cells, inhibiting NF-kappaB in these cells has little or no effect on inducing apoptosis. We previously showed that heme oxygenase-1 (HO-1) underlies this resistance of AML to tumor necrosis factor-induced apoptosis. Here, we describe a mechanism by which HO-1 is a silent antiapoptotic factor only revealed when NF-kappaB is inhibited, thus providing a secondary antiapoptotic mechanism to ensure AML cell survival and chemoresistance. We show that inhibition of NF-kappaB increased HO-1 expression in primary AML cells compared with that of nonmalignant cells. In addition, we observed this suppressed HO-1 level in AML cells compared with CD34(+) nonmalignant control cells. Using chromatin immunoprecipitation assay and small interfering RNA knockdown, we showed that the NF-kappaB subunits p50 and p65 control this suppression of HO-1 in AML cells. Finally, we showed that inhibition of HO-1 and NF-kappaB in combination significantly induced apoptosis in AML cells but not in noncancerous control cells. Thus, NF-kappaB inhibition combined with HO-1 inhibition potentially provides a novel therapeutic approach to treat chemotherapy-resistant forms of AML.

Item Type: Article
Uncontrolled Keywords: acute disease,antineoplastic agents,apoptosis,chromatin immunoprecipitation,enzyme induction,heme oxygenase-1,humans,leukemia, myeloid,nf-e2-related factor 2,nf-kappa b,nf-kappa b p50 subunit,nitriles,promoter regions, genetic,reactive oxygen species,sulfones,transcription factor rela,tumor cells, cultured
Faculty \ School: Faculty of Science > School of Pharmacy
Faculty of Medicine and Health Sciences > Norwich Medical School
University of East Anglia > Faculty of Medicine and Health Sciences > Research Groups > Prostate Cancer Studies
Faculty of Science > School of Chemical Sciences and Pharmacy
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Depositing User: Rachel Smith
Date Deposited: 05 Apr 2011 16:28
Last Modified: 25 Jul 2018 04:13
URI: https://ueaeprints.uea.ac.uk/id/eprint/28092
DOI: 10.1158/0008-5472.CAN-09-3407

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