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Updated: May 12, 2026

Polysome Fractionation and Analysis of Mammalian Translatomes on a Genome-wide Scale
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Published on: May 17, 2014

Deciphering the systems biology of mTOR inhibition by integrative transcriptome analysis

Sophie Domhan, Christian Schwager, Quanxiang Wei

  • 1Translational Radiation Oncology [E210], National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. a.amir@dkfz.de.

Current Pharmaceutical Design
|March 28, 2013
PubMed

Insights

Rapamycin derivative (RAD001) inhibits mTOR signaling, showing anti-tumor and anti-angiogenic effects. It downregulates key genes involved in angiogenesis and extracellular matrix remodeling, offering new cancer therapy insights.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • The mechanistic target of rapamycin (mTOR) signaling pathway regulates cellular homeostasis, balancing catabolic and anabolic processes.
  • mTOR inhibitors, initially used as immunosuppressants, are now explored for cancer therapy.
  • Understanding the molecular mechanisms of mTOR inhibition is crucial for optimizing its therapeutic applications.

Purpose of the Study:

  • To systematically analyze the molecular mechanisms behind the pleiotropic effects of mTOR signaling inhibition using rapamycin derivative (RAD001).
  • To identify key genetic players mediating the anti-tumor and anti-angiogenic effects of RAD001.

Main Methods:

  • Proliferation and clonogenic survival assays to determine cellular sensitivity to RAD001.
  • Co-culture experiments to assess anti-angiogenic effects.
  • U87 glioblastoma tumor xenografts to evaluate in vivo anti-tumor efficacy.
  • Integrative transcriptome analysis to decipher molecular mechanisms.

Main Results:

  • RAD001 demonstrated preferential sensitivity in human microvascular endothelial cells (HDMVEC), fibroblasts, and U87 glioblastoma cells, while lung and prostate tumor cells showed resistance.
  • RAD001 exhibited potent anti-angiogenic effects by inhibiting endothelial cell tube formation in co-culture models.
  • Transcriptome analysis revealed a predominant downregulation of genes involved in angiogenesis and extracellular matrix remodeling, including VEGF, HIF1A, and NRP1.
  • RAD001 treatment also downregulated key components of PI3K/mTOR signaling, such as PDK1, SGK1, and NDRG.

Conclusions:

  • RAD001 effectively inhibits tumor growth and angiogenesis through the downregulation of specific genetic networks.
  • The study identified key genetic participants responsible for the anti-tumor and anti-angiogenic actions of mTOR inhibition.
  • Shared mechanisms between RAD001 and mycophenolic acid suggest potential for combined therapeutic strategies.

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