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The arachidonic acid-LTB4-BLT2 pathway enhances human B-CLL aggressiveness.

Abstract : Deregulation of the oxidative cascade of poly-unsaturated fatty acids (PUFAs) has been associated with several cancers, including chronic lymphocytic leukemia (B-CLL). Leukotriene B4 (LTB4), a metabolite of arachidonic acid (AA), is produced by B-CLL and contributes to their survival. The aim of the present study was to analyze the activity of the oxidative cascade of PUFAs in B-CLL. Purified B cells from patients and normal B CD5 positive cells were subjected to flow cytometry, Western-blot and RT-qPCR analyses. LTB4 plasma and intracellular concentrations were determined by ELISA. Our results showed that aggressive B-CLL tumor cells, i.e. cells with an annual proliferation index above 2, over-expressed calcium-dependent and calcium-independent phospholipases A2 (cPLA2-alpha and iPLA2-beta, respectively), 5-lipoxygenase (5LOX) and leukotriene A4 hydroxylase (LTA4H). Intracellular LTB4 levels were lower in the most aggressive cells than in cells with a smaller proliferation index, despite equivalent plasma levels, and lower expression of cytochrome P450 4F3A (CYP4F3A), one major enzyme involved in LTB4 inactivation. Since BLT2, a LTB4 membrane receptor was also more often expressed on aggressive tumor cells, and since a BLT2 inhibitor significantly impaired B-CLL viability in vitro, we propose that LTB4 was efficiently trapped onto BLT2 present on aggressive tumors, thereby eliciting an autocrine response. Taken together our results demonstrate a major deregulation of the pathway leading to LTB4 synthesis and degradation in B-CLL cells, and provide a framework for understanding how these modifications promote cell survival and proliferation, especially in the most aggressive BCLL.
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https://hal.univ-brest.fr/hal-01256598
Contributor : Ghislaine Calvez <>
Submitted on : Friday, January 15, 2016 - 9:44:15 AM
Last modification on : Monday, February 25, 2019 - 3:14:16 PM

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Nathalie Guriec, Catherine Le Jossic-Corcos, Brigitte Simon, Jean-Christophe Ianotto, Adrian Tempescul, et al.. The arachidonic acid-LTB4-BLT2 pathway enhances human B-CLL aggressiveness.. BBA - Biochimica et Biophysica Acta, Elsevier, 2014, 1842 (11), pp.2096-105. ⟨10.1016/j.bbadis.2014.07.016⟩. ⟨hal-01256598⟩

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