The Connectivity Map Links Iron Regulatory Protein-1–Mediated Inhibition of Hypoxia-Inducible Factor-2a Translation to the Anti-inflammatory 15-deoxy-Δ12,14-Prostaglandin J2

Cancer Research - Tập 70 Số 8 - Trang 3071-3079 - 2010
Michael Zimmer1,2,3, Justin Lamb1,4,2,3, Benjamin L. Ebert1,2,3, Mary C. Lynch1,4,2,3, Neil Christopher1,2,3, Emmett V. Schmidt1,4,2,3, Todd R. Golub1,4,2,3, Othon Iliopoulos1,2,3
1Authors' Affiliations: 1Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts; 2Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital; 3The Pediatric Service, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center; 4Harvard Stem Cell Institute, Brigham and Women's Hospital, Boston, Massachusetts; and 5The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts
2The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts
3The Pediatric Service, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center
4Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital

Tóm tắt

Abstract Hypoxia-inducible factors 1 and 2 (HIF1 and HIF2) are heterodimeric transcription factors consisting of α regulatory subunits and a constitutively expressed β subunit. The expression of α regulatory subunits is promoted by hypoxia, cancer-associated mutations, and inflammatory cytokines. Thus, HIF1 and HIF2 provide a molecular link between cancer and inflammation. We have recently identified novel small molecules that selectively inhibit translation of the HIF2a message and thereby powerfully inhibit the expression of HIF2a target genes. We report here that Connectivity Map analysis links three of these compounds to the anti-inflammatory cytokine 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2). As with our identified compounds, PGJ2 inhibits translation of the HIF2a message in a mammalian target of rapamycin–independent manner by promoting the binding of iron regulatory protein-1 (IRP1) to a noncanonical iron responsive element (IRE) embedded within the 5′-untranslated region of the HIF2a message. The IRE is necessary and sufficient for mediating the effect. Mutation of the IRE sequence, or downregulation of IRP1 expression, blocks the effect of PGJ2 on HIF2a translation. This is the first report of an endogenous natural molecule regulating HIF2a translation, and it suggests that part of the anti-inflammatory and putative antineoplastic effects of PGJ2 may be mediated through inhibition of HIF2a within tumor epithelial cells themselves and/or mesenchymal cells of the tumor microenvironment. Cancer Res; 70(8); 3071–9. ©2010 AACR.

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Cancer Research

Tập 70 Số 8

3071-3079

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