Research Papers:

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

Stuart A Rushworth, Lyubov Zaitseva, Susana Langa, Kristian M Bowles and David J MacEwan _

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Oncotarget. 2010; 1:359-366. https://doi.org/10.18632/oncotarget.168

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Received: August 20, 2010, Accepted: September 3, 2010, Published: September 13, 2010

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-κBdependent 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.


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