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-1a (HIF-1a), 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-1a. Our study investigated whether hemin and other protoporphyrin compounds have the ability to inhibit HIF-1a activity, and if so, what is the molecular basis of inhibition. Hemin treatment prevented CoCl 2 -induced HIF-1a expression. HIF-1a 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-1a-dependent gene transactivation. Intriguingly, hemin directly impeded the binding between heat shock protein 90 (HSP90) and HIF-1a, 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-1a 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-1a 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.

Modulation of hypoxia-inducible factors (HIF) from an integrative pharmacological perspective

“…Inhibitors of Hsp90 activity such as geldanamycin in HMEC-1 cells and the monkey kidney fibroblast cell line COS-7 [134] and Radicicol also affect HRE binding by the HIF-1a and HIF-1b heterodimer [81]. In addition, the iron-binding porphyrin hemin inhibits HIF-1a-dependent gene transactivation through its binding with Hsp90 in HCT116 cells [135]. The metabolite actinomycin D, an inhibitor of transcription was shown to abolish hypoxia-induced HIF-1a binding activity in Hep3B cells [11].…”

MPT0B098, a Novel Microtubule Inhibitor That Destabilizes the Hypoxia-Inducible Factor-1α mRNA through Decreasing Nuclear–Cytoplasmic Translocation of RNA-Binding Protein HuR

“…Accumulated data have shown that most HIF-1a inhibitors target HIF-1a by either promoting HIF-1a protein degradation or inhibiting its translation (26). Several agents have been described that may affect the rate of protein synthesis, including topoisomerase I (27) and II poisons (28), cyclindependent kinase (29), Hsp90 (30)(31)(32), and microtubuledisrupting agents (16). However, recent studies have suggested that levels of HIF-1a mRNA may be a limiting factor affecting protein translation when cells were incubated under a hypoxic condition (33).…”

Biallelic inactivation of protoporphyrinogen oxidase and hydroxymethylbilane synthase is associated with liver cancer in acute porphyrias

“…Therefore, it is probable that a dysfunctional heme synthesis, due to a biallelic inactivation of enzymes, could play a role in initiating carcinogenesis and tumor progression [6,15,16]. Undoubtedly, further studies are needed to confirm the second-hit model in other patients, to completely understand the mechanism of HCC in AHP.…”

“…Recently, it has been shown that hemin, the oxidative form of heme, has anti-inflammatory and anti-tumorigenic effects. More specifically, protoporphyrin IX, the product of the enzymatic reaction catalyzed by PPOX, was shown to have an inhibitory effect on hypoxia inducible factor-1a (HIF-1a) [6,15]. HIF-1a activation promotes cancer progression by upregulation of target genes, which induce tumor cell proliferation [14].…”