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BMC Proceedings

, 7:P19 | Cite as

Targeting uroporphyrinogen decarboxylase for head and neck cancer treatment

  • Emma Ito
  • Shijun Yue
  • Eduardo H Moriyama
  • Angela B Hui
  • Inki Kim
  • Wei Shi
  • Nehad M Alajez
  • Nirmal Bhogal
  • GuoHua Li
  • Alessandro Datti
  • Aaron D Schimmer
  • Brian C Wilson
  • Peter P Liu
  • Daniel Durocher
  • Benjamin G Neel
  • Brian O’Sullivan
  • Bernard Cummings
  • Rob Bristow
  • Jeff Wrana
  • Fei-Fei Liu
Open Access
Poster presentation

Keywords

Surrounding Normal Tissue Heme Biosynthesis Radiosensitizing Effect Enhance Tumor Cell FaDu Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Background

Head and neck cancer (HNC) is the 8th most common malignancy worldwide. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, underscoring a need to develop novel therapeutic approaches, particularly those that enhance tumor cell death, while minimizing damage to the surrounding normal tissues.

Materials and methods

An RNA interference (RNAi)-based high-throughput screen (HTS) was performed for the large-scale identification of novel genes that will selectively sensitize HNC cells to ionizing radiation. The Dharmacon Protein Kinase and Druggable Genome siRNA Libraries were screened using FaDu cells (human hypopharyngeal squamous cell cancer). Radiosensitizing targets were subjected to in vitro and in vivo characterizations.

Results

Sixty-seven target sequences with potential radiosensitizing effects were identified. Targets reducing the surviving fraction by >50% at 2 Gy relative to their un-irradiated counterparts were selected for further evaluation. A key regulator of heme biosynthesis, uroporphyrinogen decarboxylase (UROD), was thereby identified as a novel tumor-selective radiosensitizing target, demonstrating both in vitro and in vivo efficacy. Radiosensitization appeared to be mediated via enhancement of tumor oxidative stress from perturbation of iron homeostasis and increased free radical production. UROD was significantly over-expressed in HNC patient biopsies, wherein lower pre-radiation mRNA levels correlated with improved survival, suggesting UROD could potentially predict radiation response. UROD down-regulation also radiosensitized several different human cancer models, while sparing normal cells.

Conclusions

An RNAi-based radiosensitizer HTS has revealed UROD as a potent tumor-selective sensitizer for radiation, with potential relevance to many human malignancies.

Financial support

Canadian Institutes of Health Research (CIHR; grant 69023); Elia Chair in Head and Neck Cancer Research; philanthropic support from Wharton Family, J. Finley, and G. Tozer; Campbell Family Institute for Cancer Research; Ministry of Health and Long-Term Planning; CIHR Resource Maintenance grant (PRG-82679).

Copyright information

© Ito et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors and Affiliations

  • Emma Ito
    • 1
    • 2
  • Shijun Yue
    • 2
  • Eduardo H Moriyama
    • 1
  • Angela B Hui
    • 2
  • Inki Kim
    • 2
  • Wei Shi
    • 2
  • Nehad M Alajez
    • 2
  • Nirmal Bhogal
    • 2
  • GuoHua Li
    • 3
  • Alessandro Datti
    • 4
    • 5
  • Aaron D Schimmer
    • 1
    • 2
  • Brian C Wilson
    • 1
  • Peter P Liu
    • 3
  • Daniel Durocher
    • 4
  • Benjamin G Neel
    • 1
    • 2
  • Brian O’Sullivan
    • 6
    • 7
  • Bernard Cummings
    • 6
    • 7
  • Rob Bristow
    • 1
    • 2
    • 6
    • 7
  • Jeff Wrana
    • 4
  • Fei-Fei Liu
    • 1
    • 2
    • 6
    • 7
  1. 1.Department of Medical BiophysicsUniversity of TorontoTorontoCanada
  2. 2.Ontario Cancer InstituteCampbell Family Cancer Research Institute, University Health NetworkTorontoCanada
  3. 3.Toronto General Research InstituteUniversity Health NetworkTorontoCanada
  4. 4.Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  5. 5.Department of Experimental Medicine and Biochemical SciencesUniversity of PerugiaPerugiaItaly
  6. 6.Department of Radiation Oncology, Princess Margaret HospitalUniversity Health NetworkTorontoCanada
  7. 7.Department of Radiation OncologyUniversity of TorontoTorontoCanada

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