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Survivin as a therapeutic target for radiation sensitization in lung cancer

Bo Lu1, Yi Mu, Carolyn Cao

  • 1Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. bo.lu@vanderbilt.edu

Cancer Research
|April 17, 2004
PubMed

Insights

Radiation down-regulates survivin (a protein promoting cell survival) in normal endothelial cells but not cancer cells. This suggests survivin is a potential therapeutic target to enhance radiotherapy effectiveness.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Radiotherapy

Background:

  • Survivin expression is elevated in malignancies and associated with radiation resistance.
  • Understanding survivin regulation by radiation is crucial for developing novel cancer therapies.

Purpose of the Study:

  • To investigate the effect of radiation on survivin expression in primary endothelial cells and malignant cell lines.
  • To elucidate the molecular mechanisms underlying radiation-induced survivin regulation.
  • To evaluate survivin's role in radioresistance and its potential as a therapeutic target.

Main Methods:

  • Irradiation of human umbilical vein endothelial cells (HUVECs) and tumor cell lines.
  • Western blot analysis for survivin protein levels.
  • Flow cytometry for cell cycle analysis.
  • Quantitative real-time PCR for survivin mRNA levels.
  • Luciferase reporter gene assays to assess promoter activity.
  • Gene transfection for p53 and survivin overexpression/inhibition.

Main Results:

  • Radiation (3 Gy) significantly reduced survivin protein and mRNA levels in HUVECs, but not in tumor cell lines.
  • Survivin down-regulation by radiation was transcriptionally mediated and independent of the cell cycle.
  • Radiation suppressed the survivin promoter, and this effect was not dependent on p53 in HUVECs.
  • Survivin overexpression conferred radioresistance by inhibiting apoptosis and increasing cell viability.
  • Inhibition of survivin sensitized cancer cells to radiation.

Conclusions:

  • Radiation transcriptionally down-regulates survivin in normal endothelial cells via a p53-independent mechanism.
  • This regulatory pathway is defective in malignancies, contributing to radioresistance.
  • Targeting survivin could overcome radioresistance and enhance the efficacy of radiotherapy.

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