Open AccessIron facilitator LS 081 reduces hypoxia‐inducible factor‐1α protein and functions as anticancer agent in hepatocellular carcinoma
Author(s) -
Tanaka Hiroki,
Li Zhen,
Ikuta Katsuya,
Addo Lynda,
Akutsu Hiroaki,
Nakamura Masao,
Sasaki Katsunori,
Ohtake Takaaki,
Fujiya Mikihiro,
Torimoto Yoshihiro,
Glass Jonathan,
Kohgo Yutaka
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.02192.x
Subject(s) - hepatocellular carcinoma , hydroxylation , hypoxia inducible factors , cancer research , cell culture , in vivo , chemistry , transfection , biology , biochemistry , enzyme , gene , genetics , microbiology and biotechnology
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, LS 081, 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 LS 081. In the human hepatocellular carcinoma cell lines H ep3 B and HepG2 , a combination of LS 081 and ferric ammonium citrate ( LS 081/ F e AC ) 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 HEK 293 cells, was not affected by the combination of LS081 and F e AC . Furthermore, the iron‐facilitating activity of LS 081 resulted in H ep3 B and H ep G 2 growth inhibition in vitro and in vivo . These results indicate that the iron‐facilitating activity of LS 081 inhibits HIF ‐1α expression through prolyl‐hydroxylation of HIF ‐1α and might have a therapeutic effect in the treatment of hepatocellular carcinoma. ( Cancer Sci 2012; 103: 767–774)