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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma

Syed A Ali1, Verline Justilien1, Lee Jamieson1

  • 1Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA.

Cancer Cell
|March 16, 2016
PubMed

Insights

Protein kinase Cι (PKCι) drives lung adenocarcinoma (LADC) by activating NOTCH3 expression via the ELF3 transcription factor. Targeting this PKCι-ELF3-NOTCH3 pathway shows promise for treating KRAS-mutated LADC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • KRAS-mediated lung adenocarcinoma (LADC) is a significant clinical challenge.
  • Tumor stemness and asymmetric cell division are critical for LADC initiation and maintenance.
  • The role of protein kinase Cι (PKCι) in LADC stemness is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which PKCι regulates stemness in LADC.
  • To investigate the role of the NOTCH3 pathway in PKCι-driven LADC.
  • To evaluate the therapeutic potential of targeting the PKCι-ELF3-NOTCH3 signaling axis.

Main Methods:

  • Investigated the interaction between PKCι, ELF3, and NOTCH3 in LADC cells.
  • Assessed ELF3 occupancy on the NOTCH3 promoter using chromatin immunoprecipitation assays.
  • Examined the effect of PKCι and NOTCH inhibition on asymmetric cell division and tumor growth in vitro and in vivo.

Main Results:

  • PKCι oncogene controls NOTCH3 expression, a key driver of stemness in KRAS-mutated LADC.
  • PKCι phosphorylates ELF3, enhancing its binding to the NOTCH3 promoter, thereby activating NOTCH3 expression.
  • PKCι-ELF3-NOTCH3 signaling regulates asymmetric cell division, crucial for tumor initiation and maintenance.
  • Combined blockade of PKCι and NOTCH synergistically inhibited LADC cell tumorigenicity and tumor growth.

Conclusions:

  • The PKCι-ELF3-NOTCH3 signaling pathway is a critical regulator of stemness and tumorigenesis in KRAS-mutated LADC.
  • Targeting this pathway offers a promising therapeutic strategy for KRAS LADC.
  • Pharmacologic inhibition of PKCι and NOTCH demonstrates significant therapeutic potential.
Keywords:
ELF3KRAS-driven lung adenocarcinomaNOTCH signalingprotein kinase Cιtherapeutic intervention

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