title: Activation of nuclear factor κB (NF-κB) in prostate cancer is mediated by protein kinase C epsilon (PKCepsilon).
abstract: Protein kinase C ε (PKCε) has emerged as an oncogenic kinase and plays important roles in cell survival, mitogenesis and invasion. PKCε is up-regulated in most epithelial cancers, including prostate, breast, and lung cancer. Here we report that PKCε is an essential mediator of NF-κB activation in prostate cancer cells. A strong correlation exists between PKCε overexpression and NF-κB activation status in prostate cancer cells. Moreover, transgenic overexpression of PKCε in the mouse prostate causes preneoplastic lesions that display significant NF-κB hyperactivation. PKCε RNAi depletion or inhibition in prostate cancer cells diminishes NF-κB translocation to the nucleus with subsequent impairment of both activation of NF-κB transcription and induction of NF-κB responsive genes in response to the proinflammatory cytokine tumor necrosis factor α (TNFα). On the other hand, PKCε overexpression in normal prostate cells enhances activation of the NF-κB pathway. A mechanistic analysis revealed that TNFα activates PKCε via a C1 domain/diacylglycerol-dependent mechanism that involves phosphatidylcholine-phospholipase C. Moreover, PKCε facilitates the assembly of the TNF receptor-I signaling complex to trigger NF-κB activation. Our studies identified a molecular link between PKCε and NF-κB that controls key responses implicated in prostate cancer progression.
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rachana
authors.initials: R
authors.lastname: Garg
authors.forename: Jorge
authors.initials: J
authors.lastname: Blando
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Perez
authors.forename: HongBin
authors.initials: H
authors.lastname: Wang
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Benavides
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Kazanietz
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000378:metabolism; D011485:Protein Binding; D051744:Protein Kinase C-epsilon / Q000378:metabolism* / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498143:RELA protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D049410:Luciferases, Renilla; D051744:Protein Kinase C-epsilon; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C