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

Abstract

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-d, 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 dominantnegative expression) of PKC-d confirm a role for this PKC isoform in EGF-dependent COX-2 induction. Overexpression of a functional PKC-d enhanced COX-2 expression indicating that PKC-d 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-d by EGF while inhibition of PKC-d had no discernible effects on p38-MAPK activation. Finally, EGF stimulation promotes physical interactions between PKC-d and Sp1 resulting in phosphorylation and nuclear localization of this transcription factor. These data provide the first evidence that PKC-d is a critical link between p38-MAPK and Sp1-dependent COX-2 expression in human glioma cells.

Celecoxib Can Induce Vascular Endothelial Growth Factor Expression and Tumor Angiogenesis

“…In fact, blocking this transcription factor with mithramycin A or siRNA significantly inhibits p38-MAPK-dependent VEGF promoter activation and expression. These results are consistent with our previous findings that EGF-dependent activation of the p38-MAPK signaling pathway positively regulates Sp1 activity and further increases COX-2 expression in glioma cells (18,28). Here, the EGFR/p38-MAPK/Sp1 signaling axis similarly increases VEGF levels, confirming the importance of this pathway in VEGF regulation.…”

“…We previously found that EGF-induced COX-2 expression in glioma cells required p38-MAPK-dependent activation of the Sp1 transcription factor (18,28). VEGF expression is similarly induced by EGF in various systems (29)(30)(31).…”

Targeting PKCδ-mediated topoisomerase IIβ overexpression subverts the differentiation block in a retinoic acid-resistant APL cell line

“…51,52 In particular, the p38 MAP kinase is phosphorylated and activated by RA treatment in NB4 cells 53 and PRKCD phosphorylation at Thr505 was recently shown to be dependent upon p38. 54 However, RA activates many complex signaling cascades that may also lie upstream of PRKCD and TOP2B. Indeed, future directions will aim to elucidate more clearly the entire signaling pathway leading to TOP2B regulation.…”

Viewing cancer pathophysiology as a lead in understanding cardiac and vascular disease mechanisms

“…Non-steroidal anti-inflammatory agents (NSAIDs) target Cox-2 and PKC delta, a prosurvival pathway both in cancer [66] and the heart [65] and interfere with this infarct-sparing mechanism. Cox-2/EGFR/MAPK signal cascade acts in cancer [67] as well as being a pro-hypertrophic mechanism in the heart [68].…”