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Prolyl-tRNA synthetase inhibition promotes cell death in SK-MEL-2 cells through GCN2-ATF4 pathway activation

Takeo Arita1, Megumi Morimoto1, Yukiko Yamamoto1

  • 1Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.

Biochemical and Biophysical Research Communications
|January 15, 2017
PubMed

Insights

A novel prolyl tRNA synthetase (PRS) inhibitor, T-3861174, effectively triggers cancer cell death and reduces tumor growth by activating the GCN2-ATF4 pathway, offering a promising new cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cancer cells exhibit heightened protein translation, supporting their survival and proliferation.
  • Targeting protein synthesis is a potential anti-cancer strategy.
  • Prolyl tRNA synthetase (PRS) is crucial for protein synthesis.

Purpose of the Study:

  • To investigate the anti-cancer effects of a novel small molecule PRS inhibitor, T-3861174.
  • To elucidate the mechanism of T-3861174-induced cancer cell death.
  • To evaluate the therapeutic potential of T-3861174 in preclinical cancer models.

Main Methods:

  • Treatment of various tumor cell lines, including SK-MEL-2, with T-3861174.
  • Analysis of translation levels and cell death pathways.
  • Assessment of the GCN2-ATF4 pathway activation.
  • Evaluation of anti-tumor activity in xenograft models.

Main Results:

  • T-3861174 induced cell death in tumor cell lines without completely inhibiting translation.
  • T-3861174-induced cell death was mediated by the activation of the GCN2-ATF4 pathway.
  • T-3861174 demonstrated significant anti-tumor activity in xenograft models with minimal weight loss.

Conclusions:

  • Prolyl tRNA synthetase (PRS) is a druggable target for cancer therapy.
  • T-3861174 is a potential therapeutic agent for cancer treatment.
  • Targeting PRS offers a novel strategy for cancer therapy.
Keywords:
CHOPGCN2-ATF4Prolyl tRNA synthetaseTranslationtRNA synthetase

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