Iron depletion in HCT116 cells diminishes the upregulatory effect of phenethyl isothiocyanate on heme oxygenase-1

Abstract

Some of the health-promoting properties of cruciferous vegetables are thought to be partly attributed to isothiocyanates. These phytochemicals can upregulate the expression of certain cytoprotective stress genes, but it is unknown if a particular nutrient is involved. Herein, the objective was to ascertain if adequate iron is needed for enabling HCT116 cells to optimally express heme oxygenase-1 (HO-1) when induced by phenethyl isothiocyanate (PEITC). PEITC increased HO-1 expression and also nuclear translocation of Nrf2, which is a transcription factor known to activate the HO-1 gene. However, in HCT116 cells that were made iron-deficient by depleting intracellular iron with deferoxamine (DFO), PEITC was less able to increase HO-1 expression and nuclear translocation of Nrf2. These suppressive effects of DFO were overcome by replenishing the iron-deficient cells with the missing iron. To elucidate these findings, it was found that PEITC-induced HO-1 upregulation can be inhibited with thiol antioxidants (glutathione and N-acetylcysteine). Furthermore, NADPH oxidase inhibitors (diphenyleneiodonium and apocynin) and a superoxide scavenger (Tiron) each inhibited PEITC-induced HO-1 upregulation. In doing so, diphenyleneiodonium was the most potent and also inhibited nuclear translocation of redox-sensitive Nrf2. Collectively, the results imply that the HO-1 upregulation by PEITC involves an iron-dependent, oxidant signaling pathway. Therefore, it is concluded that ample iron is required to enable PEITC to fully upregulate HO-1 expression in HCT116 cells. As such, it is conceivable that iron-deficient individuals may not reap the full health benefits of eating PEITC-containing cruciferous vegetables that via HO-1 may help protect against multiple chronic diseases.

Dietary Iron Intake and HIV-Related Outcomes Among Adults Initiating Antiretroviral Therapy in Tanzania

“…ID impairs the immune response in PLWHIV by limiting heme oxygenase expression and activity in response to infection. 47 Heme, the by-product of heme oxygenase activity, slows the growth of HIV and Mycobacteriae . 48 ID also lowers B-cell proliferation and the production of antibodies, 49 which mediate cytotoxicity and suppress viremia to slow down HIV disease progression.…”

MiR-20b Down-Regulates Intestinal Ferroportin Expression In Vitro and In Vivo

“…Iron is absorbed and transported into the systemic circulation through the proximal small intestinal epithelium, primarily the duodenum in mammals [53,54]. In recent years, no mature duodenal cell lines have been found, while HCT116 and Caco-2 cells are commonly used for intestinal iron absorption and transportation [55,56,57,58,59]. Moreover, there are many studies on the function of miRNAs in HCT116 and Caco-2 cells.…”

Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

“…Taken together, activators of the NRF2/HO‐1 axis that additionally reduce GPX4 expression have promising cancer cell selectivity and, when given as combination therapy with conventional drugs, might even protect normal cells. However, their cytotoxic effects seem to depend on the genetic background and metabolic state of the cells as well as the extent and potential duration of HO‐1 upregulation 288 . The bivalent role of HO‐1 on ferroptosis is not fully understood but seems to be tightly associated with the iron state of cancer cells 289 .…”

“…However, their cytotoxic effects seem to depend on the genetic background and metabolic state of the cells as well as the extent and potential duration of HO‐1 upregulation. 288 The bivalent role of HO‐1 on ferroptosis is not fully understood but seems to be tightly associated with the iron state of cancer cells. 289 We speculate that the higher iron status of cancer cells compared to normal cells as well as their dependency on GPX4‐protective mechanisms against lipid peroxidation contribute to the selective toxicity of combined GPX4‐suppressing and HO‐1‐inducing compounds toward malignant cells.…”