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Disruption of the HIF‐1α/p300 interaction as a means of inhibiting angiogenesis
Author(s) -
Reece Kelie M,
Richardson Emily D,
Pisle Stephen T,
Holly Alesia J,
Campbell Tessa J,
Figg William D
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.613.3
Subject(s) - angiogenesis , hypoxia (environmental) , transcription factor , cancer research , downregulation and upregulation , mediator , chemistry , hypoxia inducible factors , hif1a , coactivator , microbiology and biotechnology , biology , biochemistry , oxygen , gene , organic chemistry
Solid tumors develop regions of hypoxia because of an imbalance in oxygen supply and consumption. Thus, adaptation of cancer cells to hypoxia is critical for tumor survival. The most important mediator of the cell's response to reduced oxygen is the hypoxia inducible factor‐1 (HIF‐1) transcription factor. Due to the involvement of HIF in tumor progression and angiogenesis, inhibition of HIF‐mediated transcription has the potential for treatment of cancer. Since p300 is a crucial coactivator of hypoxia‐inducible transcription, disruption of the HIF‐1α/p300 complex is desirable as a selective mechanism of inhibiting HIF activity. Previous data have shown that several members of the epidithiodiketopiperazine (ETP) family of natural products, namely, chetomin, chaetocin, and gliotoxin, block the interaction between HIF‐1α and p300. We performed a series of rat aortic ring assays and found that ETP treatment had antiangiogenic effects, apparently through disruption of the HIF‐1α/p300 complex, as ETPs blocked co‐immunoprecipitation of HIF‐1α and p300. Aortic rings were immunostained for HIF‐1α to confirm its upregulation. These results show the potential of targeting this interaction in cancer therapeutics. We are currently using mouse xenografts to test the effects of these ETPs on tumor growth, and thus determine the feasibility of moving these compounds forward into pre‐clinical development.