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G3BP1 controls the senescence-associated secretome and its impact on cancer progression

Amr Omer1,2, Monica Cruz Barrera3, Julian L Moran1,2

  • 1Department of Biochemistry, McGill University, Montreal, QC, H3G1Y6, Canada.

Nature Communications
|October 6, 2020
PubMed

Insights

RasGAP SH3-binding protein 1 (G3BP1) drives the harmful effects of cellular senescence by promoting the senescent-associated secretory phenotype (SASP). Inhibiting G3BP1 reduces SASP, impairing cancer growth without affecting senescence itself.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Oncology

Background:

  • Cellular senescence contributes to cancer and aging but is also vital for physiological functions.
  • Mechanisms controlling senescence's detrimental effects while preserving benefits remain unclear.

Purpose of the Study:

  • Investigate the role of rasGAP SH3-binding protein 1 (G3BP1) in regulating the senescent-associated secretory phenotype (SASP).
  • Determine if targeting G3BP1 can mitigate negative senescence outcomes like cancer promotion.

Main Methods:

  • Studied G3BP1's role in activating SASP during senescence.
  • Examined G3BP1's mechanism involving cyclic GMP-AMP synthase (cGAS) and cytosolic chromatin.
  • Assessed the impact of G3BP1 depletion or inhibition on SASP, NF-κB, and STAT3 pathways.
  • Evaluated the effect of "SASPless" senescent cells on cancer cell proliferation and tumor growth in vitro and in vivo.

Main Results:

  • G3BP1 is essential for activating the SASP.
  • G3BP1 promotes SASP by linking cGAS to cytosolic chromatin, activating NF-κB and STAT3.
  • G3BP1 inhibition or depletion blocks SASP without altering senescence.
  • Senescent cells lacking SASP (SASPless) inhibit cancer cell growth and tumor progression.

Conclusions:

  • G3BP1 is a key regulator required for SASP expression.
  • SASP secretion is a critical mediator of senescence-associated tumor growth.
  • Targeting G3BP1 offers a strategy to decouple detrimental SASP effects from beneficial senescence functions.

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