title: FLIP regulation of HO-1 and TNF signalling in human acute myeloid leukemia provides a unique secondary anti-apoptotic mechanism.
abstract: Acute myeloid leukemia (AML) comprises a heterogeneous group of clonal disorders of hematopoietic progenitors. We previously showed that heme oxygenase-1 (HO-1/Hsp32) underlies resistance of AML to TNF-induced apoptosis. Here we show for the first time that the modulatory protein, FLICE-inhibitory protein (FLIP) indirectly regulates induction of HO-1 in response to TNF in human AML blasts, but not non-cancerous control cells. In AML cells, TNF-induced FLIP expression was an NF-κB-dependent event, and silencing of FLIP isoforms (FLIPL, FLIPS and FLIPR) induced pro-apoptotic responses to TNF, with FLIPL knock-down providing the greatest apoptotic switch. However, FLIPL knock-down consequently increased expression of HO-1; a response that occurred in AML (but not non-cancerous) cells to protect a proportion of them from apoptotic death. Our results show that increases in HO-1 induced an apoptotic-resistant form in AML cells in the absence of FLIPL. This is the first time that FLIPL has been shown to regulate the expression of HO-1. These data reveal unique regulatory networks in cancerous AML cells whereby FLIP regulation of HO-1 provides AML cells with secondary anti-apoptotic protection against extrinsic factors (eg TNF/chemotherapies) that try to switch on death signals in these highly death-resistant cells. Future AML therapies should target these mechanisms.
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Rushworth
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom.
authors.forename: Lyubov
authors.initials: L
authors.lastname: Zaitseva
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom.
authors.forename: Susana
authors.initials: S
authors.lastname: Langa
authors.affiliation: Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Colney Lane, Norwich, NR4 7UY, United Kingdom.
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Bowles
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: MacEwan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1