title: Iron facilitator LS081 reduces hypoxia-inducible factor-1α protein and functions as anticancer agent in hepatocellular carcinoma.
abstract: Hypoxia inducible factor-1α (HIF-1α) has a central role in cellular oxygen-sensing, and its overexpression in many types of cancer is considered important in tumor progression. Thus, targeting HIF-1α production and activity has been of great therapeutic interest. In normoxic conditions, HIF-1α is hydroxylated by oxygen-dependent prolyl-hydroxylases, which require ferrous iron for its activity. The tumor suppressor protein von Hippel Lindau binds to the hydroxylated HIF-1α, which is then ubiquitinated and degraded by proteasomes. We focused on the physiological degradation machinery of HIF-1α mediated by prolyl hydroxylases. Previously, we identified a small molecule, LS081, that is capable of stimulating iron uptake into cells. In the present study, we aimed to inhibit the expression of HIF-1α protein and growth of hepatocellular carcinoma by using the iron-facilitating activity of LS081. In the human hepatocellular carcinoma cell lines Hep3B and HepG2, a combination of LS081 and ferric ammonium citrate (LS081/FeAC) inhibited HIF-1α protein expression but did not inhibit HIF-1α mRNA expression. A mutated HIF-1α protein, which has proline residues that were replaced with alanine and transfected into HEK293 cells, was not affected by the combination of LS081 and FeAC. Furthermore, the iron-facilitating activity of LS081 resulted in Hep3B and HepG2 growth inhibition in vitro and in vivo. These results indicate that the iron-facilitating activity of LS081 inhibits HIF-1α expression through prolyl-hydroxylation of HIF-1α and might have a therapeutic effect in the treatment of hepatocellular carcinoma.
authors.affiliation: Department of Gastrointestinal Immunology and Regenerative Medicine, Asahikawa Medical University, Asahikawa, Japan. hiroki-t@asahikawa-med.ac.jp
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ikuta
authors.forename: Lynda
authors.initials: L
authors.lastname: Addo
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Akutsu
authors.forename: Masao
authors.initials: M
authors.lastname: Nakamura
authors.forename: Katsunori
authors.initials: K
authors.lastname: Sasaki
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ohtake
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Fujiya
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Torimoto
authors.forename: Jonathan
authors.initials: J
authors.lastname: Glass
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohgo
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D006835:Hydrazones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C559818:LS 081; D012333:RNA, Messenger; D009536:Niacinamide; D007501:Iron