title: Regulation of the viability of Nf1 deficient cells by PKC isoforms.
abstract: Suppression of protein kinase C (PKC) is known to be synthetically lethal with ras mutations in various types of cancer cells. The studies also showed that blockade of PKC affected the viability of Nf1 deficient cells. Since PKC family consists of more than 10 isoforms, our study aimed at identifying which isoform(s) played the crucial role in sensitizing Nf1 deficient cells to apoptosis. Using genetic and chemical PKC inhibitors, we demonstrated that the concurrent inhibition of PKC α and β induced Nf1 deficient ST or 96.2 cells, but not SNF02.2 cells with a normal Nf1 or ST cells ectopically expressing Nf1 effective domain gene, to apoptosis. In this process, PKC δ in Nf1 deficient cells, but not in ST/Nf1 cells, was upregulated and translocated to the nucleus. Furthermore, caspase 3 was cleaved and cytochrome c was released to the cytosol. Thus, it appeared that PKC δ and α/β are the crucial components for sustaining the aberrant Ras signaling and further viability of Nf1 deficient cells. The abrogation of these two isoforms activated their opponent PKC δ for switching on the caspase 3-governed apoptotic machinery.
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, USA. The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.affiliation: The Institute of Clinical Sciences, Gothenburg University, Gothenburg, SE.
authors.forename: Toshima
authors.initials: T
authors.lastname: Parris
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, USA.
authors.forename: Junchi
authors.initials: J
authors.lastname: Huang
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, USA. The Jiangxi Province Tumor Hospital, Nanchang, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yi
authors.affiliation: The Institute of Clinical Sciences, Gothenburg University, Gothenburg, SE.
authors.forename: Khalil
authors.initials: K
authors.lastname: Helou
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, USA. The Institute of Clinical Sciences, Gothenburg University, Gothenburg, SE.
authors.forename: Changyan
authors.initials: C
authors.lastname: Chen
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D025542:Neurofibromin 1 / Q000172:deficiency* / Q000235:genetics; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D025542:Neurofibromin 1; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D045304:Cytochromes c; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D020169:Caspases; D018631:ras Proteins