Iron facilitator LS081 reduces hypoxia-inducible factor-1α protein and functions as anticancer agent in hepatocellular carcinoma
| Autor: | Takaaki Ohtake, Hiroaki Akutsu, Lynda Addo, Zhen Li, Yutaka Kohgo, Hiroki Tanaka, Masao Nakamura, Jonathan Glass, Yoshihiro Torimoto, Katsunori Sasaki, Katsuya Ikuta, Mikihiro Fujiya |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Niacinamide
Cancer Research Carcinoma Hepatocellular Iron Biology Hydroxylation Cell Line Mice chemistry.chemical_compound Animals Humans RNA Messenger Cell Proliferation Cell growth HEK 293 cells Hydrazones Original Articles Hep G2 Cells General Medicine Transfection Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology HEK293 Cells Oncology Hypoxia-inducible factors chemistry Proteasome Cell culture Tumor progression Cancer research Growth inhibition |
| Zdroj: | Cancer Sci |
| ISSN: | 1347-9032 |
| DOI: | 10.1111/j.1349-7006.2011.02192.x |
| Popis: | Author 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text