Atypical protein kinase Cι as a human oncogene and therapeutic target.
Protein kinase inhibitors represent a major class of targeted therapeutics that has made a positive impact on treatment of cancer and other disease indications. Among the promising kinase targets for further therapeutic development are members of the Protein Kinase C (PKC) family. The PKCs are central components of many signaling pathways that regulate diverse cellular functions including proliferation, cell cycle, differentiation, survival, cell migration, and polarity. Genetic manipulation of individual PKC isozymes has demonstrated that they often fulfill distinct, nonredundant cellular functions. Participation of PKC members in different intracellular signaling pathways reflects responses to varying extracellular stimuli, intracellular localization, tissue distribution, phosphorylation status, and intermolecular interactions. PKC activity, localization, phosphorylation, and/or expression are often altered in human tumors, and PKC isozymes have been implicated in various aspects of transformation, including uncontrolled proliferation, migration, invasion, metastasis, angiogenesis, and resistance to apoptosis. Despite the strong relationship between PKC isozymes and cancer, to date only atypical PKCiota has been shown to function as a bona fide oncogene, and as such is a particularly attractive therapeutic target for cancer treatment. In this review, we discuss the role of PKCiota in transformation and describe mechanism-based approaches to therapeutically target oncogenic PKCiota signaling in cancer.
London Research Institute, Lincoln's Inn Fields, London WC2A 3LY, UK; King's College London, Guy's Campus, London, UK.
Peter J
PJ
Parker
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, 45400 San Pablo Road, Jacksonville, FL 32224, USA.
Verline
V
Justilien
London Research Institute, Lincoln's Inn Fields, London WC2A 3LY, UK.
Philippe
P
Riou
London Research Institute, Lincoln's Inn Fields, London WC2A 3LY, UK; Royal Marsden Hospital, Fulham Road, London, UK.
Mark
M
Linch
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, 45400 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: Fields.Alan@mayo.edu.
Alan P
AP
Fields
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009857:Oncogenes / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D000099293:Protein Kinase C-lambda
D007527:Isoenzymes; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D000099293:Protein Kinase C-lambda
Atypical Protein Kinase Cι; Cellular transformation; Mechanism-based therapeutics; Oncogenic signaling; Phox-Bem1 (PB1) domain