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Attenuation of TORC1 signaling delays replicative and oncogenic RAS-induced senescence

Marina Kolesnichenko1, Lixin Hong, Rong Liao

  • 1Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA. marinak@scripps.edu

Cell Cycle (Georgetown, Tex.)
|May 26, 2012
PubMed

Insights

Inhibiting the target of rapamycin complex 1 (TORC1) pathway can delay or reverse cellular senescence, a key barrier against cancer. This suggests TORC1 is crucial for mediating senescence signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Cellular senescence, a state of proliferative arrest, acts as a tumor suppressor by preventing uncontrolled cell division.
  • However, oncogene-induced senescence can paradoxically promote cellular transformation, highlighting a complex role in cancer development.
  • Several oncogenes implicated in senescence converge on the target of rapamycin (TOR) pathway.

Purpose of the Study:

  • To investigate whether attenuating the TOR pathway influences the onset or progression of cellular senescence.
  • To determine the specific role of TOR Complex 1 (TORC1) and TOR Complex 2 (TORC2) in mediating senescence.

Main Methods:

  • Utilized primary human fibroblasts undergoing replicative or oncogenic RAS-induced senescence.
  • Inhibited TOR signaling using the drug rapamycin or by genetically depleting TORC1.
  • Assessed the effects of TORC1 inhibition and TORC2 depletion on senescence phenotypes.

Main Results:

  • Inhibition of TORC1, via rapamycin or depletion, delayed and partially reversed established senescence.
  • Depletion of TORC2 did not impact replicative or RAS-induced senescence.
  • Overexpression of REDD1, a TORC1 inhibitor, delayed the onset of replicative senescence.

Conclusions:

  • TORC1 is an integral component of the signaling pathway that mediates cellular senescence.
  • Targeting TORC1 represents a potential strategy for modulating senescence in cancer prevention or therapy.

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