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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

Interaction between ERK and GSK3beta mediates basic fibroblast growth factor-induced apoptosis in SK-N-MC

Cuiling Ma1, Kimberly A Bower, Gang Chen

  • 1Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Morgantown, WV 26506, USA.

The Journal of Biological Chemistry
|February 12, 2008
PubMed

Insights

Basic fibroblast growth factor (FGF2) triggers apoptosis in Ewing's sarcoma family of tumors (ESFT) cells. FGF2 causes cytoplasmic accumulation of phosphorylated ERK1/2 (pERK1/2) by forming a complex with GSK3beta, leading to cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Ewing's sarcoma family of tumors (ESFT) are aggressive cancers.
  • Basic fibroblast growth factor (FGF2) exhibits anti-proliferative and pro-apoptotic effects on ESFT cells.
  • The precise molecular mechanisms underlying FGF2's action in ESFT remain largely unelucidated.

Purpose of the Study:

  • To investigate the signaling pathways involved in FGF2-induced apoptosis of ESFT cells.
  • To elucidate the role of ERK and GSK3beta in FGF2-mediated cell death.
  • To determine the subcellular localization of key signaling molecules in response to FGF2.

Main Methods:

  • Utilized a human peripheral primitive neuroectodermal tumor cell line (SK-N-MC).
  • Analyzed the phosphorylation and subcellular localization of ERK1/2 and GSK3beta.
  • Employed pharmacological inhibitors (TDZD, LiCl, PD98059), kinase-deficient GSK3beta, and small interfering RNA (siRNA) to probe signaling pathways.

Main Results:

  • FGF2 stimulated cytoplasmic retention of phosphorylated ERK1/2 (pERK1/2) via association with phosphorylated GSK3beta (pGSK3beta(Tyr-216)).
  • Inhibition of GSK3beta or ERK, or disruption of the ERK-GSK3beta complex, led to nuclear translocation of pERK1/2 and protected cells from apoptosis.
  • Overexpression of wild-type GSK3beta sensitized cells to FGF2-induced apoptosis, while kinase-deficient GSK3beta or GSK3beta siRNA conferred protection.

Conclusions:

  • FGF2-induced cytoplasmic accumulation of pERK1/2, mediated by an ERK-GSK3beta complex, is cytotoxic to ESFT cells.
  • Disruption of this cytoplasmic complex promotes pERK1/2 nuclear translocation and confers resistance to FGF2-induced cell death.
  • Targeting the ERK-GSK3beta interaction may represent a therapeutic strategy for ESFT.

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