Ghrelin promotes intestinal epithelial cell proliferation through PI3K/Akt pathway and EGFR trans-activation both converging to ERK 1/2 phosphorylation

Peptides. 2014 Feb;52:113-21. doi: 10.1016/j.peptides.2013.11.021. Epub 2013 Dec 21.

Abstract

Little is known about ghrelin's effects on intestinal epithelial cells even though it is known to be a mitogen for a variety of other cell types. Because ghrelin is released in close proximity to the proliferative compartment of the intestinal tract, we hypothesized that ghrelin may have potent pro-proliferative effect on intestinal epithelial cells as well. To test this hypothesis, we characterized the effects of ghrelin on FHs74Int and Caco-2 intestinal epithelial cell lines in vitro. We found that ghrelin has potent dose dependent proliferative effects in both cell lines through a yet to be characterized G protein coupled growth hormone secretagogue receptor (GHS-R) subtype. Consistent with above findings, cell cycle flowcytometric analyses demonstrated that ghrelin shifts cells from the G1 to S phase and thereby promotes cell cycle progression. Further characterization of subcellular events, suggested that ghrelin mediates its pro-proliferative effect through Adenylate cyclase (AC)-independent epidermal growth factor receptor (EGFR) trans-activation and PI3K-Akt phosphorylation. Both these pathways converge to stimulate MAPK, ERK 1/2 downstream. The role of ghrelin in states where intestinal mucosal injury and rapid mucosal repair occur warrants further investigation.

Keywords: Ghrelin; Intestinal cells; Proliferation; Signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Caco-2 Cells
  • Dose-Response Relationship, Drug
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • ErbB Receptors / metabolism*
  • G1 Phase / drug effects*
  • Ghrelin / pharmacology*
  • Humans
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / metabolism*
  • MAP Kinase Signaling System / drug effects*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • S Phase / drug effects*
  • Transcriptional Activation / drug effects*

Substances

  • Ghrelin
  • Phosphatidylinositol 3-Kinases
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3