title: Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor.
abstract: The discovery in the 1980s that protein kinase C (PKC) is a receptor for the tumor-promoting phorbol esters fueled the dogma that PKC is an oncoprotein. Yet 30+ years of clinical trials for cancer using PKC inhibitors not only failed, but in some instances worsened patient outcome. The recent analysis of cancer-associated mutations, from diverse cancers and throughout the PKC family, revealed that PKC isozymes are generally inactivated in cancer, supporting a tumor suppressive function. In keeping with a bona fide tumor suppressive role, germline causal loss-of-function (LOF) mutations in one isozyme have recently been identified in lymphoproliferative disorders. Thus, strategies in cancer treatment should focus on restoring rather than inhibiting PKC.
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0721, USA. Electronic address: anewton@ucsd.edu.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Newton
authors.affiliation: Laboratory of Cell and Developmental Signaling, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Cancer Research UK Manchester Institute, Manchester, UK. Electronic address: john.brognard@nih.gov.
authors.forename: John
authors.initials: J
authors.lastname: Brognard
mesh_terms: D000818:Animals; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics*; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011493:Protein Kinase C
keywords: LOF; PKC; diacylglycerol; phorbol esters; tumor suppressor