FLIP regulation of HO-1 and TNF signalling in human acute myeloid leukemia provides a unique secondary anti-apoptotic mechanism

Rushworth, Stuart A., Zaitseva, Lyubov, Langa Marcano, Susana, Bowles, Kristian M. ORCID: https://orcid.org/0000-0003-1334-4526 and MacEwan, David J. (2010) FLIP regulation of HO-1 and TNF signalling in human acute myeloid leukemia provides a unique secondary anti-apoptotic mechanism. Oncotarget, 1 (5). pp. 359-366. ISSN 1949-2553

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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 noncancerous control cells. In AML cells, TNF-induced FLIP expression was an NF-?Bdependent 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.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Pharmacy
Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Depositing User: Rachel Smith
Date Deposited: 05 Apr 2011 16:03
Last Modified: 22 Dec 2022 11:31
URI: https://ueaeprints.uea.ac.uk/id/eprint/28111
DOI: 10.18632/oncotarget.168

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