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Cancer Cell. 2016 Mar 14;29(3):367-378. doi: 10.1016/j.ccell.2016.02.012.

Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma.

Author information

1
Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA.
2
Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA. Electronic address: fields.alan@mayo.edu.

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.

KEYWORDS:

ELF3; KRAS-driven lung adenocarcinoma; NOTCH signaling; protein kinase Cι; therapeutic intervention

PMID:
26977885
PMCID:
PMC4795153
DOI:
10.1016/j.ccell.2016.02.012
[Indexed for MEDLINE]
Free PMC Article

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