HIF-dependent antitumorigenic effect of antioxidants in vivo.
The antitumorigenic activity of antioxidants has been presumed to arise from their ability to squelch DNA damage and genomic instability mediated by reactive oxygen species (ROS). Here, we report that antioxidants inhibited three tumorigenic models in vivo. Inhibition of a MYC-dependent human B lymphoma model was unassociated with genomic instability but was linked to diminished hypoxia-inducible factor (HIF)-1 levels in a prolyl hydroxylase 2 and von Hippel-Lindau protein-dependent manner. Ectopic expression of an oxygen-independent, stabilized HIF-1 mutant rescued lymphoma xenografts from inhibition by two antioxidants: N-acetylcysteine and vitamin C. These findings challenge the paradigm that antioxidants diminish tumorigenesis primarily through decreasing DNA damage and mutations and provide significant support for a key antitumorigenic effect of diminishing HIF levels.
Gao
Ping
P
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Zhang
Huafeng
H
Dinavahi
Ramani
R
Li
Feng
F
Xiang
Yan
Y
Raman
Venu
V
Bhujwalla
Zaver M
ZM
Felsher
Dean W
DW
Cheng
Linzhao
L
Pevsner
Jonathan
J
Lee
Linda A
LA
Semenza
Gregg L
GL
Dang
Chi V
CV
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D002460:Cell Line; D042822:Genomic Instability; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation