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

ABSTRACT: We report that the protein kinase C? (PKC?) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKC? activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKC?-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 PKC?-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKC? and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKC?-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC.

SUBMITTER: Ali SA 

PROVIDER: S-EPMC4795153 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature