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A Semi-Quantitative Drug Affinity Responsive Target Stability (DARTS) assay for studying Rapamycin/mTOR interaction
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The mTOR inhibitor rapamycin suppresses DNA double-strand break repair

Honghong Chen1, Zhefu Ma, Robert P Vanderwaal

  • 1Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Blvd., St. Louis, MO 63108, USA.

Radiation Research
|January 28, 2011
PubMed

Insights

Mammalian target of rapamycin (mTOR) inhibitors like rapamycin suppress DNA repair pathways, enhancing cancer cell radiosensitivity. This study reveals mTOR inhibition disrupts homologous recombination and nonhomologous end joining, crucial for repairing radiation-induced DNA damage.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mammalian target of rapamycin (mTOR) signaling is implicated in numerous cancers.
  • mTOR inhibitors are investigated for cancer therapy due to their potential radiosensitization effects.
  • The precise molecular mechanisms underlying mTOR inhibitor-mediated radiosensitization remain unclear.

Purpose of the Study:

  • To investigate the molecular basis of radiosensitization by mTOR inhibitors.
  • To determine the effect of rapamycin on DNA double-strand break (DSB) repair pathways in breast cancer cells.

Main Methods:

  • MCF7 breast cancer cells were treated with rapamycin.
  • Homologous recombination (HR) and nonhomologous end joining (NHEJ) repair pathways were assessed.
  • Recruitment of BRCA1 and Rad51 to DNA repair foci was analyzed.
  • Ionizing radiation was used to induce DNA DSBs.
  • Chromosome and chromatid breaks were quantified.

Main Results:

  • Rapamycin significantly suppressed both HR and NHEJ DNA repair mechanisms.
  • Impaired recruitment of BRCA1 and Rad51 to DNA repair foci was observed.
  • Persistent radiation-induced DSBs were detected in rapamycin-pretreated cells.
  • Increased frequency of chromosome and chromatid breaks occurred following rapamycin treatment and irradiation.

Conclusions:

  • mTOR inhibitors, exemplified by rapamycin, radiositize cancer cells by disrupting major DNA DSB repair pathways.
  • Suppression of HR and NHEJ by mTOR inhibitors contributes to their therapeutic potential in cancer treatment.
  • Targeting mTOR offers a strategy to enhance the efficacy of radiation therapy.

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