title: Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma.
abstract: We report that the protein kinase Cι (PKCι) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKCι activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKCι-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKCι and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKCι-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Ali
authors.affiliation: Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA.
authors.forename: Verline
authors.initials: V
authors.lastname: Justilien
authors.affiliation: Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Jamieson
authors.affiliation: Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Murray
authors.affiliation: Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA. Electronic address: fields.alan@mayo.edu.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Fields
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; C117307:KRAS protein, human; C499374:NOTCH3 protein, human; D050783:Proto-Oncogene Proteins c-ets; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D014157:Transcription Factors; D011493:Protein Kinase C; D016283:Proto-Oncogene Proteins p21(ras)
keywords: ELF3; KRAS-driven lung adenocarcinoma; NOTCH signaling; protein kinase Cι; therapeutic intervention