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Sustained activation of the FGF1-MEK-ERK pathway inhibits proliferation, invasion and migration and enhances

Taichi Miura1, Junko Kado1, Kazuma Ashisuke2

  • 1Regenerative Therapy Research Group, Department of Radiation Regulatory Science Research, National Institute of Radiological Sciences (NIRS), National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.

Journal of Radiation Research
|April 18, 2024
PubMed

Insights

A fibroblast growth factor 1 (FGF1) mutant inhibits angiosarcoma cell proliferation and metastasis. This mutant also enhances radiosensitivity by activating the MEK signaling pathway, offering potential new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Angiosarcoma is a rare, aggressive soft-tissue tumor with limited treatment options and poor prognosis.
  • Radiotherapy is a primary treatment, but understanding molecular mechanisms to improve efficacy is crucial.
  • Fibroblast growth factor 1 (FGF1) mutant, engineered for thermostability, shows potential in inhibiting angiosarcoma metastasis, but its mechanism is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism of action of the FGF1 mutant in inhibiting angiosarcoma cell progression.
  • To investigate the role of the MEK signaling pathway in mediating the effects of the FGF1 mutant.
  • To assess the impact of the FGF1 mutant on angiosarcoma cell radiosensitivity.

Main Methods:

  • ISOS-1 mouse angiosarcoma cells were treated with wild-type FGF1 or FGF1 mutant.
  • Cell proliferation was evaluated by cell counting over time.
  • Invasion and migration were assessed using transwell assays.
  • Radiosensitivity was determined by colony formation assays post-irradiation.
  • The effect of a MEK inhibitor in combination with the FGF1 mutant was evaluated.

Main Results:

  • The FGF1 mutant significantly inhibited ISOS-1 cell proliferation, invasion, and migration.
  • These inhibitory effects were mediated by sustained activation of FGF1 signaling.
  • A MEK inhibitor reversed the anti-proliferative, anti-invasive, and anti-migratory effects of the FGF1 mutant.
  • The FGF1 mutant enhanced ISOS-1 cell radiosensitivity, an effect diminished by MEK inhibition.
  • The FGF1 mutant was found to inhibit actin polymerization, linking cytoskeletal dynamics to radiosensitivity.

Conclusions:

  • The FGF1 mutant inhibits angiosarcoma cell proliferation, invasion, and migration via sustained MEK-mediated signaling.
  • The FGF1 mutant enhances radiosensitivity in angiosarcoma cells, also through the MEK pathway.
  • Inhibition of actin polymerization by the FGF1 mutant is associated with altered radiosensitivity.
  • These findings highlight the FGF1 mutant as a potential therapeutic agent for angiosarcoma, targeting MEK signaling.
Keywords:
FGF1MEK inhibitoractin polymerizationangiosarcoma cellsradiosensitivity

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