Protein Kinase C-θ (PKCθ), a Potential Drug Target for Therapeutic Intervention with Human T Cell Leukemias

The link between apoptosis and malignant cell growth is firmly established, and various forms of therapy in cancer, e. g., the use of DNA-damaging chemotherapeutic drugs, are based on the principle of inducing apoptosis in malignant cells. However, in many known instances, tumor cells develop resistance to apoptosis through various mechanisms. Thus, interventions designed to facilitate tumor cells apoptosis are likely to have a therapeutic benefit. PKC theta, which is expressed relatively selectively in T cells, plays an important role in mature T cell activation and proliferation upon its translocation to the plasma membrane. PKC theta is necessary for induction of the interleukin-2 (IL-2) gene because the transcription factors AP-1 and NF-kappa B, which are essential for IL-2 gene promoter activation, are main targets of PKC theta. Recent studies revealed that PKC theta provides an important survival signal that protects leukemic T cells from Fas- or UV-induced apoptosis. These findings and the constitutive localization of PKC theta in the membrane of some leukemic T cells suggests that it plays a role in leukemic T cell survival and/or proliferation, and that selective PKC theta-inhibitory strategies may facilitate elimination of malignant T cells. The high-affinity IL-2 receptor (IL-2R alpha) is a major target of receptor-directed therapy in several human diseases, and it is constitutively expressed by the malignant cells in some T cell leukemias, suggesting an autocrine IL-2/IL-2R loop that participates in the expansion of leukemic IL-2R(+) cells. Therefore, given the essential role of PKC theta in IL-2 production, IL-2 gene regulation by PKC theta could also be of therapeutic interest.