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. Ali et al. show that in KRAS-mediated lung adenocarcinoma, PKCι controls NOTCH3 expression by phosphorylating ELF3 and driving occupancy at the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the TIC phenotype and combined blockade of PKCι and NOTCH has a synergistic antitumor effect in vitro and in vivo.
Original language | English (US) |
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Pages (from-to) | 367-378 |
Number of pages | 12 |
Journal | Cancer cell |
Volume | 29 |
Issue number | 3 |
DOIs | |
State | Published - Mar 14 2016 |
Keywords
- ELF3
- KRAS-driven lung adenocarcinoma
- NOTCH signaling
- Protein kinase Cι
- Therapeutic intervention
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research