EGFR and PKC are involved in the activation of ERK1/2 and p90 RSK and the subsequent proliferation of SNU-407 colon cancer cells by muscarinic acetylcholine receptors

Mol Cell Biochem. 2012 Nov;370(1-2):191-8. doi: 10.1007/s11010-012-1410-z. Epub 2012 Aug 3.

Abstract

We have previously shown that muscarinic acetylcholine receptors (mAChRs) enhance SNU-407 colon cancer cell proliferation via the ERK1/2 pathway. Here, we examined the signaling pathways linking mAChR stimulation to ERK1/2 activation and the subsequent proliferation of SNU-407 cells. The inhibition of the epidermal growth factor receptor (EGFR) by AG1478 or protein kinase C (PKC) by GF109203X significantly reduced carbachol-stimulated ERK1/2 activation and cell proliferation. Cotreatment of the cells with AG1478 and GF109203X produced an additive effect on carbachol-stimulated ERK1/2 activation, suggesting that the EGFR and PKC pathways act in parallel. The p90 ribosomal S6 kinases (RSKs) are downstream effectors of ERK1/2 and are known to have important roles in cell proliferation. In SNU-407 cells, carbachol treatment induced RSK activation in an atropine-sensitive manner, and this RSK activation was decreased by the inhibition of either EGFR or PKC. Moreover, the RSK-specific inhibitor BRD7389 almost completely blocked carbachol-stimulated cell proliferation. Together, these data indicate that EGFR and PKC are involved in mAChR-mediated activation of ERK1/2 and RSK and the subsequent proliferation of SNU-407 colon cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Carbachol / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / pathology*
  • Enzyme Activation / drug effects
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Indoles / pharmacology
  • Maleimides / pharmacology
  • Protein Kinase C / metabolism*
  • Quinazolines
  • Quinolones / pharmacology
  • Receptors, Muscarinic / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Tyrphostins

Substances

  • BRD 7389
  • Indoles
  • Maleimides
  • Quinazolines
  • Quinolones
  • Receptors, Muscarinic
  • Tyrphostins
  • RTKI cpd
  • Carbachol
  • ErbB Receptors
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases
  • bisindolylmaleimide I
  • Calcium