The overall objectives of the current proposal are to investigate the cell type-specific regulatory mechanisms that control the expression of protein kinase C-epsilon (PKC-epsilon) in human lung cancer cells and to define what role the phenotype-specific expression of PKC-epsilon may play in the control of cell growth, transformation, and cellular response to drug treatment. Specifically, the proposed studies are designed to extend preliminary results which indicate that induction of PKC-epsilon expression may, in part, contribute to development of a drug resistant phenotype during tumor progression of small cell lung cancer (SCLC). A strategy of direct targeting PKC-epsilon expression using antisense technology as well as expression of wild type and mutant forms of PKC-epsilon will be used. A striking differential expression profile of PKC-epsilon but not other PKC isoforms, is found in human lung cancer cell lines. PKC-epsilon is expressed in all of the non-SCLC cell lines tested, but none of the SCLC cell lines. Further, its expression is induced when H82 human SCLC cell line is transformed to a non- SCLC phenotype. This transformation is accompanied with changes in drug sensitivity. Therefore, the molecular mechanisms underlying phenotype-specific expression of the PKC-epsilon isoform will be investigated in detail. The information obtained from the proposed studies should provide a better understanding of the biology of lung cancer at the molecular level. More importantly, the results may provide insight into the molecular basis of developing drug resistance, which may lead to novel antineoplastic strategies. Finally, it is expected that a more precise understanding of the regulatory mechanism of PKC-epsilon gene expression will help in the basic understanding of the role(s) PKC may play in human tumor cell proliferation, and how specific interference with PKC-mediated signaling pathways may be therapeutically exploited in the treatment of human cancer.