Novel anti-leukemic compound ingenol 3-angelate inhibits T cell apoptosis by activating PKCTHETA.

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 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 anti-apoptotic 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 anti-apoptotic proteins Mcl-1 and Bcl-xL. 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 PKC influences whether PKC activation leads to an anti- or pro-apoptotic outcome in the cell types tested.