NRF2 Blockade Suppresses Colon Tumor Angiogenesis by Inhibiting Hypoxia-Induced Activation of HIF-1 alpha

Title
NRF2 Blockade Suppresses Colon Tumor Angiogenesis by Inhibiting Hypoxia-Induced Activation of HIF-1 alpha
Author(s)
곽미경Tae-Hyoung Kim[Tae-Hyoung Kim]Eu-gene Hur[Eu-gene Hur]강수진Dinesh Thapa[Dinesh Thapa]김정애이유미[이유미]구세광[구세광]정연진[정연진]
Keywords
OXIDATIVE STRESS; GENE-EXPRESSION; OLIGONUCLEOTIDE MICROARRAY; TRANSCRIPTION FACTORS; ANTIOXIDANT RESPONSE; MOLECULAR-MECHANISMS; ADAPTIVE RESPONSE; NITRIC-OXIDE; LUNG-CANCER; HIF-ALPHA
Issue Date
201103
Publisher
AMER ASSOC CANCER RESEARCH
Citation
CANCER RESEARCH, v.71, no.6, pp.2260 - 2275
Abstract
Transcription factor NRF2 is an important modifier of cellular responses to oxidative stress. Although its cytoprotective effects are firmly established, recent evidence suggesting important roles in cancer pathobiology has yet to be mechanistically developed. In the current study, we investigated the role of NRF2 in colon tumor angiogenesis. Stable RNAi-mediated knockdown of NRF2 in human colon cancer cells suppressed tumor growth in mouse xenograft settings with a concomitant reduction in blood vessel formation and VEGF expression. Similar antiangiogenic effects of NRF2 knockdown were documented in chick chorioallantoic membrane assays and endothelial tube formation assays. Notably, NRF2-inhibited cancer cells failed to accumulate HIF-1 alpha protein under hypoxic conditions, limiting expression of VEGF and other HIF-1 alpha target genes. In these cells, HIF-1 alpha was hydroxylated but pharmacological inhibition of PHD domain-containing prolyl hydroxylases was sufficient to restore hypoxia-induced accumulation of HIF-1 alpha. Mechanistic investigations demonstrated that reduced mitochondrial O(2) consumption in NRF2-inhibited cells was probably responsible for HIF-1 alpha degradation during hypoxia; cellular O(2) consumption and ATP production were lower in NRF2 knockdown cells than in control cells. Our findings offer novel insights into how cellular responses to O2 and oxidative stress are integrated in cancer cells, and they highlight NRF2 as a candidate molecular target to control tumor angiogenesis by imposing a blockade to HIF-1 alpha signaling. Cancer Res; 71(6); 2260-75. (C)011 AACR.
URI
http://hdl.handle.net/YU.REPOSITORY/25572http://dx.doi.org/10.1158/0008-5472.CAN-10-3007
ISSN
0008-5472
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약학대학 > 약학부 > Articles
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