Inhibition of hypoxia inducible factor by phenethyl isothiocyanate

Wang, Xiu-Hong, Cavell, Breeze E., Syed Alwi, Sharifah S. and Packham, Graham (2009) Inhibition of hypoxia inducible factor by phenethyl isothiocyanate. Biochemical Pharmacology, 78 (3), 261-272. (doi:10.1016/j.bcp.2009.04.010).

Abstract

Phenethyl isothiocyanate (PEITC), a natural dietary isothiocyanate, has anti-cancer activity in various in vitro and in vivo models. PEITC inhibits angiogenesis but the molecular mechanisms that underlie this effect are not known. We have now demonstrated that PEITC is an effective inhibitor of hypoxia inducible factor (HIF), a transcription factor that plays an important role in expression of pro-angiogenic factors. PEITC inhibited the activation of a HIF-dependent reporter construct following incubation of cells in hypoxia, or treatment with the hypoxia mimetic cobalt chloride. PEITC also interfered with the accumulation of HIF1? protein and induction of the endogenous HIF target genes, CAIX, GLUT1, BNIP3 and VEGF-A. The ability of PEITC to inhibit HIF activity was independent of the activity of prolyl hydroxylases, the Von-Hippel–Landau protein and the proteasome, all of which are required for the normal rapid turnover of HIF1? in normoxia. Decreased expression of HIF1? in PEITC treated cells was not associated with changes in the levels of HIF1? RNA suggesting that PEITC may inhibit HIF activity by decreasing translation of the HIF1? RNA. Consistent with this, PEITC decreased phosphorylation of the translation regulator 4E-BP1. Our data demonstrate that PEITC is an effective inhibitor of HIF activity. This may contribute to the anti-angiogenic and anti-cancer effects of PEITC.

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Contributors

Author: Graham Packham

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