Abstract
Iron promotes the proliferation of cancer cells, but it also contributes to cell death. Here we explored whether iron could promote the Warburg effect of colorectal cancer (CRC) cells and suppress sensitivity to ferroptosis by inducing reactive oxygen species (ROS) and regulating nuclear factor erythroid 2-related factor 2 (NRF2). In this study, cell proliferation abilities were measured by CCK-8, EdU incorporation, and colony formation assays. Seahorse XF96 respirometry assays were used to detect the Warburg effect and the level of ROS was assess by DCFH-DA fluorescent probes. Results showed that iron exposure promoted the Warburg effect of CRC cells by inducing ROS and activating NRF2 both in vivo and in vitro. In addition, iron exposure also induced ferroptosis in CRC cells, but at the same time its inhibitory proteins SLC7A11 and GPX4 were also upregulated, indicating an enhanced resistance to ferroptosis. Our results revealed that iron can effectively promote tumorigenesis. Meanwhile, iron elimination or a low-iron diet might be valid therapeutic approaches for CRC.
Highlights
Colorectal cancer (CRC) is one of the deadliest cancers worldwide [1]
We speculated that high-iron diet (HID) feeding can promote the Warburg effect and exacerbate tumorigenesis
The percentage of EdU-positive cells and number of colonies in the control group increased after Ferric ammonium citrate (FAC) treatment but did not change significantly after nuclear factor erythroid 2-related factor 2 (NRF2) knockdown (Figures 5C–E). These results suggested that iron exposure promote the growth of colorectal cancer (CRC) cells by activating NRF2
Summary
Colorectal cancer (CRC) is one of the deadliest cancers worldwide [1]. Many unfavorable factors, such as aging, unhealthy dietary habits, genetic predisposition, and inflammation, increase the risk of CRC [2, 3]. On the contrary, an epidemiological study on Asian populations has revealed that zinc and heme dietary iron intakes are not associated with the progression of CRC [7]. Scientists have speculated that the oxidative stress, lipid peroxidation, and cell cycle alterations induced by iron may contribute to cancer occurrence and progression [8,9,10], but the mechanism by which iron promotes cancer cell proliferation has not been clearly defined
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