Protein Kinase Cι Expression and Oncogenic Signaling Mechanisms in Cancer

Accumulating evidence demonstrates that PKC iota is an oncogene and prognostic marker that is frequently targeted for genetic alteration in many major forms of human cancer. Functional data demonstrate that PKC iota is required for the transformed phenotype of lung, pancreatic, ovarian, prostate, colon, and brain cancer cells. Future studies will be required to determine whether PKC iota is also an oncogene in the many other cancer types that also overexpress PKC iota. Studies of PKC iota using genetically defined models of tumorigenesis have revealed a critical role for PKC iota in multiple stages of tumorigenesis, including tumor initiation, progression, and metastasis. Recent studies in a genetic model of lung adenocarcinoma suggest a role for PKC iota in transformation of lung cancer stem cells. These studies have important implications for the therapeutic use of aurothiomalate (ATM), a highly selective PKC iota signaling inhibitor currently undergoing clinical evaluation. Significant progress has been made in determining the molecular mechanisms by which PKC iota drives the transformed phenotype, particularly the central role played by the oncogenic PKC iota-Par6 complex in transformed growth and invasion, and of several PKC iota-dependent survival pathways in chemo-resistance. Future studies will be required to determine the composition and dynamics of the PKC iota-Par6 complex, and the mechanisms by which oncogenic signaling through this complex is regulated. Likewise, a better understanding of the critical downstream effectors of PKC iota in various human tumor types holds promise for identifying novel prognostic and surrogate markers of oncogenic PKC iota activity that may be clinically useful in ongoing clinical trials of ATM. J. Cell. Physiol. 226: 879-887, 2011. (C) 2010 Wiley-Liss, Inc.