Oxygen-independent degradation of HIF-alpha via bioengineered VHL tumour suppressor complex
Identificadores
URI: http://hdl.handle.net/20.500.12020/1150ISSN: 1757-4676
DOI: https://doi.org/10.1002/emmm.200900004
Autor/es
Sufan, Roxana I; Moriyama, Eduardo H; Mariampillai, Adrian; Roche, Olga; Evans, Andrew J; [et al.]Fecha
2009Tipo de documento
articleMateria/s Unesco
24 Ciencias de la VidaFichero/s
Resumen
Tumour hypoxia promotes the accumulation of the otherwise oxygen-labile
hypoxia-inducible factor (HIF)-a subunit whose expression is associated with
cancer progression, poor prognosis and resistance to conventional radiation
and chemotherapy. The oxygen-dependent degradation of HIF-a is carried out
by the von Hippel–Lindau (VHL) protein-containing E3 that directly binds and
ubiquitylates HIF-a 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-a 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-a 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 adenovirusmediated 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.