Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

The serine-threonine protein kinase, protein kinase C-delta (PKC delta), is emerging as a bi-functional regulator of cell death and proliferation. Studies in PKC delta-/- mice have confirmed :a pro-apoptotic role for this kinase in response to DNA damage and a tumor promoter role in some oncogenic contexts. In non-transformed cells, inhibition of PKC delta suppresses the release of cytochrome c and caspase activation, indicating a function upstream of apoptotic pathways. Data from PKG delta-/- mice demonstrate a role for PKC delta in the execution of DNA damage-induced and physiologic apoptosis. This has led to the important finding that inhibitors of PKC delta can be used therapeutically to reduce irradiation and chemotherapy-induced toxicity. By contrast, PKC delta is a tumor promoter in mouse models of mammary gland and lung cancer, and increased PKC delta expression is a negative prognostic indicator in Her2+ and other subtypes of human breast cancer. Understanding how these distinct functions of PM are regulated is critical for the design of therapeutics to target this pathway. This review will discuss what is currently known about biological roles of PKC delta and prospects for targeting ARCS in human disease. (C) 2016 Elsevier Inc. All rights reserved.