Inhibition of hypoxia inducible factor by phenethyl isothiocyanate.
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 HIF1alpha 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 HIF1alpha in normoxia. Decreased expression of HIF1alpha in PEITC treated cells was not associated with changes in the levels of HIF1alpha RNA suggesting that PEITC may inhibit HIF activity by decreasing translation of the HIF1alpha 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.
Cancer Research UK Clinical Centre, Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton SO166YD, UK.
Xiu-Hong
XH
Wang
Breeze E
BE
Cavell
Sharifah S
SS
Syed Alwi
Graham
G
Packham
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D017879:Isothiocyanates / Q000494:pharmacology*; D010766:Phosphorylation; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017879:Isothiocyanates; D012333:RNA, Messenger; C058305:phenethyl isothiocyanate; D011393:Procollagen-Proline Dioxygenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human