Protein kinase C-theta regulates KIT expression and proliferation in gastrointestinal stromal tumors

Oncogene. 2008 Sep 18;27(42):5624-34. doi: 10.1038/onc.2008.177. Epub 2008 Jun 2.


Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GISTs), and the KIT/PDGFRA kinase inhibitor, imatinib, is standard of care for patients with metastatic GIST. However, most of these patients eventually develop clinical resistance to imatinib and other KIT/PDGFRA kinase inhibitors and there is an urgent need to identify novel therapeutic strategies. We reported previously that protein kinase C-theta (PKCtheta) is activated in GIST, irrespective of KIT or PDGFRA mutational status, and is expressed at levels unprecedented in other mesenchymal tumors, therefore serving as a diagnostic marker of GIST. Herein, we characterize biological functions of PKCtheta in imatinib-sensitive and imatinib-resistant GISTs, showing that lentivirus-mediated PKCtheta knockdown is accompanied by inhibition of KIT expression in three KIT+/PKCtheta+ GIST cell lines, but not in a comparator KIT+/PKCtheta- Ewing's sarcoma cell line. PKCtheta knockdown in the KIT+ GISTs was associated with inhibition of the phosphatidylinositol-3-kinase/AKT signaling pathway, upregulation of the cyclin-dependent kinase inhibitors p21 and p27, antiproliferative effects due to G(1) arrest and induction of apoptosis, comparable to the effects seen after direct knockdown of KIT expression by KIT short-hairpin RNA. These novel findings highlight that PKCtheta warrants clinical evaluation as a potential therapeutic target in GISTs, including those cases containing mutations that confer resistance to KIT/PDGFRA kinase inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Base Sequence
  • Benzamides
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Gastrointestinal Stromal Tumors / pathology*
  • Humans
  • Imatinib Mesylate
  • Isoenzymes / genetics
  • Isoenzymes / physiology*
  • Molecular Sequence Data
  • Phosphorylation
  • Piperazines / pharmacology
  • Protein Kinase C / genetics
  • Protein Kinase C / physiology*
  • Protein Kinase C-theta
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / physiology*
  • Pyrimidines / pharmacology
  • RNA, Small Interfering / genetics
  • Signal Transduction


  • Benzamides
  • Isoenzymes
  • Piperazines
  • Pyrimidines
  • RNA, Small Interfering
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit
  • PRKCQ protein, human
  • Protein Kinase C
  • Protein Kinase C-theta