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Failure to Activate Cytosolic Phospholipase A₂ Causes TNF Resistance in Human Leukemic Cells

Department of Hematology, St. Bartholomew’s and Royal London School of Medicine and Dentistry, University of London, London, United Kingdom

Activation of cytosolic phospholipase A₂ (cPLA₂) by TNF has been shown to be an important component of the signaling pathway leading to cell death. The role of cPLA₂ in the cytotoxic action of TNF was investigated in a panel of human leukemic cell lines. TNF could activate cPLA₂ only in U937 and HL60 TNF-sensitive leukemic cells, but not in KG1a, CEM, and CEM/VLB₁₀₀ cells that are relatively resistant to TNF. Pretreatment with 4-bromophenacyl bromide, a cPLA₂ inhibitor, rendered U937 and HL60 cell lines resistant to the cytotoxic effect of TNF. Immunoblot and reverse-transcriptase PCR demonstrated that cPLA₂ expression was detectable at both transcriptional and translational levels in all leukemic cell lines studied, although CEM and CEM/VLB₁₀₀ cells expressed cPLA₂ mRNA and protein at lower levels. The protein synthesis inhibitor, cycloheximide, increased TNF-induced cPLA₂ activity and cytotoxicity in both CEM and CEM/VLB₁₀₀ cell lines. Low levels of cPLA₂ activity in the KG1a cell line could be activated by the cPLA₂ activator mellitin, or the calcium ionophore A23187. The data suggest that cPLA₂ activity is involved in TNF-induced cytotoxicity in leukemic cells. Resistance to TNF-induced cytotoxicity may involve either protein inhibitors that act upstream of cPLA₂ in the TNF-signaling pathway or constitutive defects of cPLA₂ itself, possibly involving calcium utilization.

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