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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Multiple anti-apoptotic pathways stimulated by EGF in cytotrophoblasts

E D Johnstone1, M Mackova, S Das

  • 1Department of Medical Microbiology and Immunology, and the University of Alberta Perinatal Research Centre, Edmonton, Alberta, Canada.

Placenta
|July 5, 2005
PubMed

Insights

Epidermal growth factor (EGF) activates multiple pathways, including JNK and sphingosine kinase-1 (SPHK-1), to reduce cytotrophoblast (CT) apoptosis. These findings reveal novel survival signaling mechanisms in trophoblast cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Reproductive Biology

Background:

  • Epidermal growth factor (EGF) is known to reduce apoptosis in primary cytotrophoblast (CT) via extracellular signal-related kinase (ERK) 1/2 and phosphatidylinositol 3-kinase (PI-3 kinase) pathways.
  • The involvement of other signaling pathways in EGF-mediated survival signaling in CT cells remains largely unknown.

Purpose of the Study:

  • To investigate the role of c-Jun NH2-terminal kinase (JNK), mitogen-activated protein kinase p38 (MAPK p38), and sphingosine kinase-1 (SPHK-1) in EGF-induced survival signaling in primary CT cells.
  • To elucidate the interplay between these pathways and the known PI-3 kinase and ERK1/2 pathways in regulating CT apoptosis.

Main Methods:

  • Primary human cytotrophoblast (CT) cells were cultured.
  • EGF treatment was applied, followed by assessment of apoptosis.
  • Specific inhibitors were used to block JNK (SP600125), p38 (SB203580), SPHK-1 (dimethyl sphingosine, DMS), and PI-3 kinase (LY294002).
  • Western blotting was used to measure protein phosphorylation (JNK, p38, Akt, ERK1/2).
  • SPHK-1 activity was measured in response to EGF and LY294002 treatment.

Main Results:

  • EGF activated both JNK and p38 pathways, indicated by increased phosphorylation.
  • Inhibition of JNK increased CT apoptosis independently of EGF, while p38 inhibition did not affect apoptosis.
  • EGF activated SPHK-1, and its inhibition with DMS increased trophoblast death.
  • SPHK-1 inhibition did not affect EGF-stimulated phosphorylation of PI-3 kinase, Akt, ERK1/2, or p38.
  • PI-3 kinase inhibition partially reduced EGF-stimulated SPHK-1 activity.

Conclusions:

  • EGF stimulates CT survival through multiple pathways, including JNK and SPHK-1, in addition to PI-3 kinase and ERK1/2.
  • The JNK and SPHK-1 pathways, but not p38, are critical for mediating the anti-apoptotic effects of EGF in CT cells.
  • These findings highlight distinct survival signaling mechanisms in trophoblast cells compared to other cell types.

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