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Open Access

Oxygen‐independent degradation of HIF‐α via bioengineered VHL tumour suppressor complex

Roxana I. Sufan, Eduardo H. Moriyama, Adrian Mariampillai, Olga Roche, Andrew J. Evans, Nehad M. Alajez, I. Alex Vitkin, Victor X. D. Yang, Fei‐Fei Liu, Brian C. Wilson, Michael Ohh

Author Affiliations

  1. Roxana I. Sufan1,
  2. Eduardo H. Moriyama2,3,
  3. Adrian Mariampillai3,
  4. Olga Roche1,
  5. Andrew J. Evans1,4,
  6. Nehad M. Alajez5,
  7. I. Alex Vitkin2,3,6,
  8. Victor X. D. Yang6,7,
  9. Fei‐Fei Liu5,
  10. Brian C. Wilson3 and
  11. Michael Ohh (michael.ohh{at}utoronto.ca) *,1
  1. 1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
  2. 2Division of Biophysics and Bioimaging, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada
  3. 3Department of Medical Biophysics, University of Toronto, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada
  4. 4Department of Pathology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada
  5. 5Department of Applied Molecular Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada
  6. 6Department of Radiation Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada
  7. 7Department of Electrical and Computer Engineering, Ryerson University, Toronto, ON, Canada
  1. *Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Tel: 416 946 7922; Fax: 416 978 5959;
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Abstract

Tumour hypoxia promotes the accumulation of the otherwise oxygen‐labile hypoxia‐inducible factor (HIF)‐α subunit whose expression is associated with cancer progression, poor prognosis and resistance to conventional radiation and chemotherapy. The oxygen‐dependent degradation of HIF‐α is carried out by the von Hippel–Lindau (VHL) protein‐containing E3 that directly binds and ubiquitylates HIF‐α for subsequent proteasomal destruction. Thus, the cellular proteins involved in the VHL–HIF pathway have been recognized as attractive molecular targets for cancer therapy. However, the various compounds designed to inhibit HIF‐α or HIF‐downstream targets, although promising, have shown limited success in the clinic. In the present study, we describe the bioengineering of VHL protein that removes the oxygen constraint in the recognition of HIF‐α while preserving its E3 enzymatic activity. Using speckle variance–optical coherence tomography (sv–OCT), we demonstrate the dramatic inhibition of angiogenesis and growth regression of human renal cell carcinoma xenografts upon adenovirus‐mediated delivery of the bioengineered VHL protein in a dorsal skin‐fold window chamber model. These findings introduce the concept and feasibility of ‘bio‐tailored’ enzymes in the treatment of HIF‐overexpressing tumours.

  • Received August 8, 2008.
  • Accepted December 12, 2008.

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