Abstract
Heme oxygenase-1 (HO-1) is an important cytoprotective gene, whose expression is known to be elevated in various carcinomas. Also, overexpression of HO-1 is known to inhibit apoptosis particularly in cancer cells. Interestingly, exposing cancer cells to certain chemopreventive agents such as isothiocyanates causes induction of HO-1, perhaps as an attempt by the cells to help them survive the stressful situation. However, it is not completely known what nutritive factors or related components in cancer cells influence HO-1 induction as caused by isothiocyanates. Thus, the aim was to test the hypothesis that adequate iron is needed to enable cancer cells to optimally express HO-1 when induced by isothiocyanates. In HCT-116 human colon adenocarcinoma cells, phenethylisothiocyanate and sulforaphane increased expression of HO-1 and also heme oxygenase activity. However, cells made iron-deficient with the iron chelator, desferrioxamine (DFO), and then exposed to isothiocyanates had much lower heme oxygenase activity. This suppressive effect of DFO on isothiocyanate-mediated induction of heme oxygenase activity was in association with repression of HO-1 protein and mRNA expression. The suppression by DFO of isothiocyanate-induced HO-1 upregulation was reversed upon replenishing the iron-deficient cells with the missing iron. Additionally, it was found that thiol antioxidants (glutathione and N-acetylcysteine) inhibited isothiocyanate-induced HO-1 upregulation, implying that the HO-1 upregulation involved an oxidant signaling pathway. Indeed, NADPH oxidase (NOX) inhibitors, namely, diphenyleneiodonium (DPI) and apocynin, and a superoxide scavenger (Tiron) inhibited isothiocyanate-induced upregulation of HO-1 as well. DPI was the most potent and also inhibited nuclear translocation of redox-sensitive Nrf-2, which is known to activate the HO-1 gene. These findings suggest the possibility that adequate amounts of iron, which at the atomic level can serve as the pivotal element of heme in NOX, must be present in the cells to permit what appears to be NOX-dependent upregulation of HO-1 by isothiocyanates. It is concluded that iron-deficient HCT-116 cells are less able to increase expression of cytoprotective HO-1 when exposed to isothiocyanates, which may make the cancer cells more susceptible to killing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5697.
- ©2010 American Association for Cancer Research
Volume 70, Issue 8 Supplement
