HO-1 underlies resistance of AML cells to TNF-induced apoptosis.
In human monocytes, tumor necrosis factor (TNF) induces a proinflammatory response. In NF-kappaB-inhibited monocytes, TNF stimulates cell death/apoptosis. In the present study, we analyzed the response of acute myeloid leukemia (AML) cells to TNF stimulation in conjunction with NF-kappaB inhibition. In all AML-derived cells tested, NF-kappaB-inhibited cells were resistant to TNF-induced apoptosis. Further investigation revealed that the cytoprotective gene heme oxygenase-1 (HO-1) was induced in NF-kappaB-inhibited AML cells in response to TNF stimulation, and HO-1 was responsible for the resistance of AML cells to the cytotoxic actions of TNF. Moreover, after transfection with HO-1 siRNA, the resistance to TNF-induced cell death signals of AML cells was removed. The HO-1 promoter region contains antioxidant-response elements that can bind the transcription factor NF-E2-related factor 2 (Nrf2). We further demonstrated that Nrf2 was activated by TNF under NF-kappaB-inhibited conditions, to play the major role in up-regulating HO-1 expression and ultimately the fate of AML cells. These results demonstrate a novel mechanism by which TNF-induced cell death is inhibited in AML cells through the induction of HO-1, via Nrf2 activation.
Rushworth
Stuart A
SA
School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, UK.
MacEwan
David J
DJ
D017209:Apoptosis / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D018922:HL-60 Cells; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1