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Resistance to TNF-Induced Cytotoxicity Correlates with an Abnormal Cleavage of Cytosolic Phospholipase A₂¹

Nour-Eddine El Mahdani^*, Maya Ameyar^*, Zhenzi Cai^*, Odile Colard, Joëlle Masliah and Salem Chouaib^2,*

^* Institut National de la Santé et de la Recherche Médicale Unité 487, Cytokines et Immunologie des Tumeurs Humaines, Institut Gustave Roussy, Villejuif, France; and Institut de la Santé et de la Recherche Médicale Unité 538, Paris, France

To investigate the mechanism underlying the absence of arachidonic acid (AA) release by TNF in TNF-resistant cells, we first performed comparative analysis of phospholipid pools in both TNF-sensitive (MCF7) and their equivalent resistant cells (C1001). Quantification and incorporation studies of [³H]AA indicated that TNF-resistant cells were not depleted in AA. Furthermore, distribution of this fatty acid in different phospholipid pools was similar in both sensitive cells and their resistant counterparts, ruling out a defect in phospholipid pools. Since phospholipase A₂ (PLA₂) are the main enzymes releasing free AA, we investigated their relative contribution in the acquisition of cell resistance to TNF-induced cell death and AA release. For this purpose, we used two PLA₂ inhibitors, methylarachidonyl fluorophosphate (MAFP) and bromoenol lactone (BEL), which selectively and irreversibly inhibit the cytosolic PLA₂ (cPLA₂) and the Ca²⁺-independent PLA₂, respectively. Although a significant inhibitory effect of MAFP on both TNF-induced AA release and PLA₂ activity in MCF7 was observed, BEL had no effect. The inhibitory effect of MAFP on cPLA₂ activity correlated with an inhibition of TNF-induced cell death. Western blot analysis revealed that TNF induced a differential cleavage of cPLA₂ in TNF-sensitive vs TNF-resistant cells. Although the p70 (70-kDa) form of cPLA₂ was specifically increased in TNF-sensitive cells, a cleaved form, p50 (50 kDa), was selectively observed in TNF-resistant C1001 cells in the presence or absence of TNF. These findings suggest that the acquisition of cell resistance to this cytokine may involve an abnormal cPLA₂ cleavage.

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