Novel antileukemic compound ingenol 3-angelate inhibits T cell apoptosis by activating protein kinase Ctheta.
Members of the protein kinase C (PKC) family of serine-threonine kinases are important regulators of immune cell survival. Ingenol 3-angelate (PEP005) activates a broad range of PKC isoforms and induces apoptosis in acute myeloid leukemia cells by activating the PKC isoform PKCdelta. We show here that, in contrast to its effect on leukemic cells, PEP005 provides a strong survival signal to resting and activated human T cells. The antiapoptotic effect depends upon the activation of PKC. This PKC isoform is expressed in T cells but is absent in myeloid cells. Further studies of the mechanism involved in this process showed that PEP005 inhibited activated CD8(+) T cell apoptosis through the activation of NFkappaB downstream of PKC, leading to increased expression of the antiapoptotic proteins Mcl-1 and Bcl-x(L). Transfection of CD8(+) T cells with dominant-negative PKC diminished the prosurvival effect of PEP005 significantly. Ectopic expression of PKC in the acute myeloid leukemia cell line NB4 turned their response to PEP005 from an increased to decreased rate of apoptosis. Therefore, in contrast to myeloid leukemia cells, PEP005 provides a strong survival signal to T cells, and the expression of functional PKC influences whether PKC activation leads to an anti- or proapoptotic outcome in the cell types tested.
Lee
Wing-Yiu
WY
Medical Research Council, Centre for Immune Regulation, Institute for Biomedical Research, School of Immunity and Infection, University of Birmingham, Birmingham B15 2TT, United Kingdom.
Hampson
Peter
P
Coulthard
Lydia
L
Ali
Farrah
F
Salmon
Mike
M
Lord
Janet M
JM
Scheel-Toellner
Dagmar
D
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy*; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D051996:Transcription Factor RelA / Q000737:chemistry
C486592:3-ingenyl angelate; D000970:Antineoplastic Agents; D004224:Diterpenes; D007527:Isoenzymes; D020033:Protein Isoforms; C498143:RELA protein, human; D051996:Transcription Factor RelA; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D053148:Caspase 3
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