Epidermal growth factor-dependent cyclooxygenase-2 induction in gliomas requires protein kinase C-delta

Oncogene. 2009 Mar 19;28(11):1410-20. doi: 10.1038/onc.2008.500. Epub 2009 Jan 26.


Earlier, we showed that epidermal growth factor receptor (EGFR) signaling in human glioma cells increased cyclooxygenase-2 (COX-2) expression through p38-mitogen-activated protein kinase (MAPK)-dependent activation of the Sp family of transcription factors. Further mechanistic details of EGFR-dependent induction of COX-2 expression in glioma cells remained elusive. Protein kinase Cs (PKCs) comprise a family of serine-threonine kinases that are major mediators of signaling from receptor tyrosine kinases. Here, we report that PKC-delta, a novel PKC isoform, plays a role in EGF-dependent COX-2 induction in human glioma cells. Pharmacological inhibition and genetic silencing (through siRNA or dominant-negative expression) of PKC-delta confirm a role for this PKC isoform in EGF-dependent COX-2 induction. Overexpression of a functional PKC-delta enhanced COX-2 expression indicating that PKC-delta is not only necessary but also sufficient to regulate COX-2 levels. Inhibition of p38-MAPK pharmacologically or with siRNA further shows that p38-MAPK is required for activation of PKC-delta by EGF while inhibition of PKC-delta had no discernible effects on p38-MAPK activation. Finally, EGF stimulation promotes physical interactions between PKC-delta and Sp1 resulting in phosphorylation and nuclear localization of this transcription factor. These data provide the first evidence that PKC-delta is a critical link between p38-MAPK and Sp1-dependent COX-2 expression in human glioma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Brain Neoplasms / enzymology*
  • Cell Line
  • Cyclooxygenase 2 / biosynthesis*
  • Cyclooxygenase 2 / genetics
  • Enzyme Induction
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / physiology
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Glioma / enzymology*
  • Humans
  • Phosphorylation
  • Protein Kinase C-delta / antagonists & inhibitors
  • Protein Kinase C-delta / physiology*
  • Sp Transcription Factors / physiology
  • Transcription, Genetic
  • p38 Mitogen-Activated Protein Kinases / physiology


  • Sp Transcription Factors
  • Epidermal Growth Factor
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • ErbB Receptors
  • Protein Kinase C-delta
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases