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INTERNATIONAL CONGRESS OF

CancerGenetics

• The role of ferroptosis in carcinogenesis

• Fatemeh keikha,¹ Hosna jami al ahmadi,² Dr. Homa Mollaei,^3,*
  1. University of Birjand
  2. University of Birjand
  3. University of Birjand
  
  
  
• Introduction: Although iron is a trace element, it plays a crucial role in cellular metabolic processes. Ferroptosis, a newly discovered form of cell death, is dependent on iron and lipid metabolism, driven by phospholipid peroxidation, and is distinct from apoptosis, necrosis, and autophagy. Ferroptosis is associated with the dysfunction of cellular antioxidant systems. The imbalance of iron metabolism homeostasis leads to an increase in intracellular free iron, which is a hallmark of ferroptosis. Studies have shown a connection between ferroptosis and tumor-associated signaling pathways, indicating that ferroptosis and epithelial-mesenchymal transition (EMT) in cancer promote each other, and ferroptosis can determine the survival and growth of cancer cells. Interestingly, treatment-resistant cancer cells, especially those in a mesenchymal state prone to metastasis, are highly vulnerable to ferroptosis.
• Methods: This review article compiles and discusses research on the role of ferroptosis in carcinogenesis. Information was sourced from databases such as PubMed, NCBI, MDPI, The Cell’s, and Google Scholar.
• Results: Excess iron can directly induce ferroptosis. The antioxidant system GPX4, a central regulator of ferroptosis, can inhibit ferroptosis by reducing lipid peroxidation. Glutathione (GSH), the cofactor for GPX4, and cysteine, a key component of GSH, are critical in this process. The reduction of GSH can be considered one of the mechanisms leading to ferroptosis. Direct or indirect inhibition of GPX4 can trigger ferroptosis. Malignant mutations in YAP2-NF signaling may predict the responsiveness of cancer cells to future ferroptosis-inducing treatments, despite the fact that these pan-caspase inhibitors effectively suppress cell death caused by other apoptotic triggers. Ferroptosis also plays a role in pathological cell death associated with degenerative diseases. In plants, ferroptosis may act as a tumor suppressor under heat stress, which could be leveraged for cancer treatment. The p53 protein can sensitize cells to ferroptosis by suppressing the expression of SLC7A11, which inhibits cystine uptake. Melanoma cells exposed to the lymphatic environment are protected from ferroptosis, enhancing their ability to survive during subsequent metastasis through the bloodstream. Promoting ferroptosis offers significant benefits for cancer prognosis. Ferroptosis was first observed using erastin to selectively kill genetically engineered cells with RAS mutations. The mechanical consequences of uncontrolled lipid peroxidation leading to ferroptotic cell death remain unclear. Fundamentally, ferroptosis can be conventionally induced by deactivating GPX4 or increasing the labile iron pool. Two mechanisms have been described for GPX4 inactivation. Additionally, recent findings suggest an unconventional ferroptosis induction pathway in the case of iron overload. The role of mitochondria in ferroptosis is established but remains ambiguous. Depending on the stimulus, ferroptosis may also involve autophagic processes. Recently, it has been proposed that oxytosis and ferroptosis should be considered as a single cell death pathway or at least have significant overlap. Induction of ferroptosis can reverse drug resistance or even overcome resistance to immunotherapy. Identifying specific vulnerabilities in cancer cells that make them prone to ferroptosis allows for more personalized treatment approaches, potentially improving outcomes. However, there is growing evidence that current ferroptosis activators can cause cell death in normal cells, leading to adverse effects during cancer treatment. Induction of ferroptosis may result in the death of stem cells and damage to bone marrow, potentially impacting hematopoiesis and leading to bone marrow suppression. Inhibition of GPX4 may have toxic effects on the liver and kidneys. Secondary tumors may emerge as a potential side effect of drug-induced ferroptosis.
• Conclusion: The findings of this review suggest that ferroptosis, as a novel form of iron-dependent and lipid metabolism-related cell death, has significant potential in cancer therapy, particularly in treatment-resistant cancer cells. While ferroptosis is associated with cancer cell death and can reverse drug resistance, there is evidence indicating that inducing ferroptosis may lead to adverse effects during cancer treatment. These effects may include damage to stem cells, bone marrow, and possibly the development of secondary tumors. Therefore, a deeper understanding of the mechanisms of ferroptosis and its effects on normal cells is essential for developing more effective and safer treatments.
• Keywords: Cell death, Ferroptosis, Iron-dependent, Carcinogenesis, Peroxidation