title: Hemin, an iron-binding porphyrin, inhibits HIF-1α induction through its binding with heat shock protein 90.
abstract: Hypoxia and growth factor stimulation induce hypoxia-inducible factor-1α (HIF-1α), conferring upon cancer cells the ability to adapt to microenvironments and enhance proliferation, angiogenesis and metastasis. Hemin, an iron-binding porphyrin, has been used to treat porphyria attacks, particularly in acute intermittent porphyria. Although the anti-inflammatory and antitumor effects of hemin were reported, no information is available regarding its effect on HIF-1α. Our study investigated whether hemin and other protoporphyrin compounds have the ability to inhibit HIF-1α activity, and if so, what is the molecular basis of inhibition. Hemin treatment prevented CoCl(2) -induced HIF-1α expression. HIF-1α inhibition by hemin resulted from an increase in its facilitated ubiquitination and degradation, as shown by the experimental results using cychloheximide treatment and ubiquitination assays. Consistently, hemin repressed HIF-1α-dependent gene transactivation. Intriguingly, hemin directly impeded the binding between heat shock protein 90 (HSP90) and HIF-1α, which was reversed by the addition of an excess amount of ATP required for HSP90 activity. In addition, hemin decreased the expression of client proteins of HSP90. Thus, the inhibition of HIF-1α activity by hemin might result from its interaction with HSP90. Moreover, treatment of protoporphyrin IX, ZnPP or Co(III)PP, but not Mn(III)PP, inhibited HIF-1α induction, indicating that protoporphyrin ring in association with the nature of binding metal leads to HSP90 inhibition. In an in vivo model, hemin treatment inhibited not only the formation of new vessels but also cancer cell proliferation and migration/invasion, supporting the notion that hemin may be applied to the prevention and/or treatment of angiogenesis and/or cancer metastasis.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Woo Hyung
authors.initials: WH
authors.lastname: Lee
authors.forename: Hee Yeon
authors.initials: HY
authors.lastname: Kay
authors.forename: Eun-sook
authors.initials: ES
authors.lastname: Kim
authors.forename: Aree
authors.initials: A
authors.lastname: Moon
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics; D011485:Protein Binding; D055550:Protein Stability; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D025801:Ubiquitin; D006427:Hemin; D007501:Iron