Iron: The Double-Edged Sword in Cancer

The Alpha Human Podcast

In this episode of the Alpha Human Podcast, Lawrence Rosenberg dives into the fascinating connection between iron overload and cancer. Iron is an essential micronutrient that plays a crucial role in various biological processes, including energy production, DNA synthesis, and immune system function. However, excess iron is also toxic and iron accumulation is typically seen in renal cell carcinoma (as well as other cancers), and increased iron metabolism is associated with the malignant transformation of cells, cancer progression, drug resistance, and immune evasion. In fact, individuals working in iron and steel occupations have a higher risk of developing kidney cancer. With that said, Lawrence also introduces a recently discovered form of programmed cell death called ferroptosis, which is induced by elevated intracellular iron levels and subsequent depletion of the antioxidant glutathione. Ferroptosis represents a natural mechanism to eliminate cancer cells, as well as those cells deficient in key nutrients or damaged by infection or ambient stress. While ferroptosis is beneficial in removing problematic cells, it should also be noted that dysregulation or excessive activation can contribute to disease pathogenesis, including neurodegenerative disorders. Interestingly, Lawrence highlights the unique characteristic of chromophobe renal cancer cells in having strikingly elevated levels of glutathione, which acts as a reactive oxygen species scavenger that protects these cells from ferroptosis. And although this metabolic dependency on glutathione enables chromophobe renal cell carcinoma (as well as a number of other cancers) to survive despite iron overload and oxidative stress, it may also turn out to be cancer's Achilles heal. 'Ferroptosis, a new form of cell death: opportunities and challenges in cancer': https://jhoonline.biomedcentral.com/articles/10.1186/s13045-019-0720-y 'Study uncovers novel treatment for chromophobe renal cell carcinoma': https://www.news-medical.net/news/20220620/Study-uncovers-novel-treatment 'Hypersensitivity to ferroptosis in chromophobe RCC is mediated by a glutathione metabolic dependency': https://www.pnas.org/doi/10.1073/pnas.2122840119 'Metabolic reprogramming and elevation of glutathione in chromophobe renal cell carcinomas': https://www.biorxiv.org/content/10.1101/649046v1.full 'The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth': https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139531/ 'Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology': https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160331/ 'Iron metabolism: State of the art in hypoxic cancer cell biology': https://www.sciencedirect.com/science/article/pii/S0003986122000844 'Iron accumulation typifies renal cell carcinoma tumorigenesis but abates with pathological progression, sarcomatoid dedifferentiation, and metastasis': https://www.frontiersin.org/articles/10.3389/fonc.2022.923043/full#B39 'Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis': https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815535/#B101 'The Two Faces of Reactive Oxygen Species in Cancer': https://www.annualreviews.org/doi/abs/10.1146/annurev-cancerbio-041916-065808 Disclaimer: The content of this podcast, and any information, advice, opinions or statements within it are not intended, and are not to be used as a substitute for professional medical advice, diagnosis, or treatment. You should not disregard or delay in obtaining medical advice for any medical condition you may have, and you should seek the assistance of a healthcare professional for any such conditions, and always inform your doctor of any changes you make, or are thinking about making to your lifestyle.