FERROPTOZ; MEKANİZMALARI VE KANSER METABOLİZMASINDAKİ ROLÜ

Öz

Ferroptoz yakın zamanda tanımlanmış, demire bağlı membran lipid peroksidasyonu ile karakterize, apoptotik olmayan bir hücre ölüm mekanizmasıdır. Morfolojik olarak, artmış mitokondriyal membran yoğunluklarına sahip normalden küçük mitokondrilerin varlığı, mitokondri kristalarının azalması veya kaybolması ve dış mitokondriyal membranın yırtılması ile karakterize edilmektedir. Ferroptozun düzenlenmesindeki hatalar; pek çok hastalığın yanı sıra onkolojik hastalıklarda da rol oynamaktadır. Bu mekanizmaların anlaşılması yeni tedavi stratejilerinin geliştirilmesi için önem taşımaktadır. Bu derlemede, ferroptozun metabolizması, aktivasyon ve inhibisyon mekanizmaları ile kanser metabolizmasındaki önemi incelenmektedir.

Anahtar Kelimeler

• ferroptozis
• hücre ölümü
• immünoterapi
• membran oksidasyonu

FERROPTOSIS; MECHANISMS AND ITS ROLE IN CANCER METABOLISM

Öz

Ferroptosis is a recently described non-apoptotic mechanism of cell death characterized by iron-dependent membrane lipid peroxidation. Morphologically, it is characterized by the presence of abnormally small mitochondria with increased mitochondrial membrane densities, reduction or disappearance of mitochondrial cristae and rupture of the outer mitochondrial membrane. Among others, in oncological diseases defects in the regulation of ferroptosis are implicated. Understanding these mechanisms is important for the development of new therapeutic strategies. This review examines the metabolism, activation and inhibition mechanisms of ferroptosis and its importance in cancer metabolism.

Anahtar Kelimeler

• ferroptosis
• cell death
• immunotherapy
• membrane oxidation

Kaynakça

1. 1. Li J, Cao F, Yin H liang, Huang Z jian, Lin Z tao, Mao N, vd. Ferroptosis: past, present and future. C. 11, Cell Death and Disease. Springer Nature; 2020.
2. 2. Tang D, Kroemer G, Kang R. Ferroptosis in immunostimulation and immunosuppression. C. 321, Immunological Reveews. John Wiley and Sons Inc; 2024. s. 199-210.
3. 3. Dixon SJ, Olzmann JA. The cell biology of ferroptoses. Nature Reveews Molecular Cell Biology. Nature Research; 2024.
4. 4. Li D, Le Y. The interacteon between ferroptoses and lipid metabolism in cancer. C. 5, Signal Transduction and Targeted Therapy. Springer Nature; 2020.
5. 5. Dolma S, Lessnick SL, Hahn WC, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells.
6. 6. Yang WS, Stockwell BR. Synthetic Lethal Screening Identifies Compounds Activating Iron-Dependent, Nonapoptotic Cell Death in Oncogenic-RAS-Harboring Cancer Cells. Chem Biol. 21 Mart 2008;15(3):234-45.
7. 7. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, vd. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 25 Mayıs 2012;149(5):1060-72.
8. 8. Dixon SJ, Pratt DA. Ferroptosis: A Flexible Constellation of Related Biochemical Mechanisms Graphical Abstract HHS Public Access.

9. 9. Conrad M, Lorenz SM, Proneth B. Targeting Ferroptosis: New Hope for As-YetIncurable Diseases. C. 27, Trends in Molecular Medicine. Elsevier Ltd; 2021. s. 113-22.
10. 10. Shi L, Liu Y, Li M, Luo Z. Emerging roles of ferroptosis in the tumor immune landscape: from danger signals to anti-tumor immunity. C. 289, FEBS Journal. John Wiley and Sons Inc; 2022. s. 3655-65.
11. 11. Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, vd. Ferroptosis: Process and function. C. 23, Cell Death and Differentiation. Nature Publishing Group; 2016. s. 369-79.
12. 12. Salnikow K. Role of iron in cancer. Semin Cancer Biol. 01 Kasım 2021;76:189-94.
13. 13. Yuan J, Ofengeim D. A guide to cell death pathways. Nature Reviews Molecular Cell Biology. Nature Research; 2023.
14. 14. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, vd. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. C. 171, Cell. Cell Press; 2017. s. 273-85.
15. 15. Xie Y, Kang R, Klionsky DJ, Tang D. GPX4 in cell death, autophagy, and disease. C. 19, Autophagy. Taylor and Francis Ltd.; 2023. s. 2621-38.
16. 16. 16. Yang WS, Sriramaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, vd.
17. 17. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1-2):317-31.
18. 18. 17. Lin Z, Liu J, Kang R, Yang M, Tang D. Lipid Metabolism in Ferroptosis. C. 5,