Upregulation of lipocortin 1 inhibits tumour necrosis factor-induced apoptosis in human leukaemic cells: a possible mechanism of resistance to immune surveillance.
The signal transduction pathway through which tumour necrosis factor (TNF) induces apoptosis in leukaemic cells may involve activation of cytosolic phospholipase A(2) (cPLA(2)). The steroids dexamethasone (Dex) and 1,25(OH)(2) D(3) both render U937 leukaemic cells resistant to TNF-induced apoptosis. In this study, we found that Dex inhibited both spontaneous and TNF-induced activation of cPLA(2). Dex had no direct effect on cellular cPLA(2) levels, but facilitated cPLA(2) degradation upon subsequent stimulation of cells with TNF. In addition, Dex increased synthesis of the endogenous cPLA(2) inhibitor lipocortin 1 (LC1). An antisense oligonucleotide to LC1 could completely abrogate Dex-induced resistance to the cytotoxic action of TNF. Constitutive LC1 levels were relatively higher in myeloid leukaemic blasts showing resistance to TNF than TNF-sensitive myeloid leukaemic cell lines. Our data suggest that Dex confers the resistance of U937 cells to TNF-induced apoptosis by upregulating intracellular levels of LC1 and by facilitating a negative-feedback loop, which is activated upon stimulation with TNF. High constitutive levels of LC1 in leukaemic blasts may protect them against immune-mediated killing.
Wu
Y L
YL
Department of Haematology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK.
Jiang
X R
XR
Lillington
D M
DM
Newland
A C
AC
Kelsey
S M
SM
D000208:Acute Disease; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism; D005246:Feedback; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007938:Leukemia / Q000378:metabolism*; D007948:Leukemia, Monocytic, Acute / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D017305:Annexin A1; D018931:Antineoplastic Agents, Hormonal; D004791:Enzyme Inhibitors; D007476:Ionophores; D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D000001:Calcimycin; D003907:Dexamethasone; D010741:Phospholipases A