Iron Regulates the Warburg Effect and Ferroptosis in Colorectal Cancer

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.

Ferroptosis: A Double-Edged Sword in Gastrointestinal Disease

“…These evidence indicate an intimate relationship between ferroptosis and IBD. In addition, dietary iron decreased the expression of SLC7A11 and GPX4 through nuclear factor erythroid 2-related factor 2 (NRF2) and enhanced resistance to ferroptosis in CRC cells [117]. Thus, a low-iron diet could be a therapeutic method for the treatment of CRC.…”

Iron Metabolism and Immune Regulation

“…However, disruption of iron homeostasis is linked to the disorders of nervous, cardiovascular, and hematological systems ( 5 ). Indeed, multiple diseases including infection, cancer, and aging diseases appear to be associated with iron homeostasis ( 6 – 8 ). Notably, iron homeostasis also influences immune system, including innate and adaptive immunity ( 6 ).…”

Long Non-Coding RNA Signatures Associated with Ferroptosis Predict Prognosis in Colorectal Cancer

“…24 Ferroptosis is a newly discovered mechanism of cell death, which is likely to give a new insight into cancer treatment strategy. 25 This scientific research explores the biomarkers of ferroptosis that could predict and analyze colorectal cancer, which could benefit cancer treatment exploration. Nevertheless, if the conditions are permitted, it would be perfect and essential to verify the prognosis prediction model established in this study.…”