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

Stuart A Rushworth, Kristian M Bowles, Prahlad Raninga, David J MacEwan

Research output: Contribution to journalArticle

53 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2973-2983
Number of pages11
JournalCancer Research
Volume70
Issue number7
DOIs
Publication statusPublished - 1 Apr 2010

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

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