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Updated: Jun 4, 2025

Visualization of G3BP Stress Granules Dynamics in Live Primary Cells
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Visualization of G3BP Stress Granules Dynamics in Live Primary Cells

Published on: May 21, 2014

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G3BP1/2-Targeting PROTAC Disrupts Stress Granules Dependent ATF4 Migracytosis as Cancer Therapy

Ting Dong1,2, Fabao Zhao3, Mengmeng Wang2

  • 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2A Nanwei Road, Xicheng District, Beijing 100050, China.

Journal of the American Chemical Society
|December 23, 2024
PubMed

Insights

New compounds targeting stress granules (SGs) inhibit cancer growth by blocking the transfer of the survival factor ATF4 from fibroblasts to tumor cells. This discovery offers novel therapeutic strategies for cancer treatment.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Stress granules (SGs) are dynamic cytoplasmic structures formed under cellular stress.
  • Activating transcription factor 4 (ATF4) is preferentially translated within SGs to promote cell survival.
  • The role of SGs and ATF4 in cancer progression within the tumor microenvironment is not fully understood.

Purpose of the Study:

  • To investigate the role of stress granules in cancer cell proliferation.
  • To develop small molecules targeting SG dynamics for cancer therapy.
  • To elucidate the mechanism of ATF4 delivery via SGs in fibroblast-mediated tumor growth.

Main Methods:

  • Design and synthesis of small molecules (#129 and PT-129) targeting G3BP1/2.
  • Inhibition of stress granule formation and disassembly of pre-existing SGs.
  • In vitro and in vivo assays to assess the effect of PT-129 on cancer cell growth and tumor progression.
  • Investigation of ATF4 delivery mechanisms via migracytosis.

Main Results:

  • Compounds #129 and PT-129 effectively inhibit SG formation and disassemble existing SGs.
  • Pharmacological inhibition of SGs by PT-129 suppressed fibroblast-mediated cancer cell growth in vitro.
  • PT-129 treatment reduced tumor growth in vivo.
  • Stress granules facilitate ATF4 delivery from fibroblasts to tumor cells through migracytosis, which is disrupted by PT-129.

Conclusions:

  • Stress granules play a critical role in promoting cancer cell proliferation by mediating ATF4 delivery.
  • Targeting G3BP1/2 and modulating SG dynamics with compounds like PT-129 presents a promising therapeutic strategy for cancer.
  • These findings provide new molecular insights into SG function and their therapeutic potential in oncology.

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