• Ferroptosis is a form of cell death, which involves iron and is different from apoptosis
  • Immune cells use this pathway to kill cancer cells
  • This provides new insight to the way the immune system works
  • Enhancing ferroptosis will provide immunotherapy with improved results for cancer patients

Introduction – In 2012 scientists discovered a new form of cell death and named it ferroptosis. This name comes from the Greek word “ptosis” which means “to fall” and the Latin word “ferrum” which refers to the iron used in this pathway (1). The key words here are: lipid oxidation. This is achieved by the accumulation of the enzyme lipid peroxidase. The process involves radical molecules that cause lipid degeneration by taking up electrons from lipid molecules. This in turn causes the lipid oxidation. Ferroptosis is a regulatory form of cell death, that occurs in pathologic cells only. The enzyme responsible for this activity is called Glutathione Peroxidase 4(GP4). Its job is to repair the lipid molecules after oxidation. However, during pathology this enzyme undergoes loss of activity, which in turn drives the ferroptosis (2).

Latest ResearchFerroptosis is seen in cells that undergo pathological activity i.e.- brain and cancer cells. Since the brain has a higher oxygen consumption and lipid content. Neuron cells are at a higher risk for lipid oxidation (3) ; causing irreversible neuronal damage. It is for this reason that patients that use chemotherapy agents such as erastin may have cognitive  dysfunction(4)(5).

Fig.1 shows how the chemotherapy agent erastin cause injury to neuron cells. Image adapted from (6)

Mechanism of action – The CD8+ T cells as part of cellular immunity, have one of the most important roles in destroying the cancer cells. They induce cell death by perforating the cell membrane through very powerful enzymes-like the granzyme, or other routes such as FAS-FAS ligand pathway (7) (8).

Fig.2 Image shows T cell( green) fighting cancer cell (blue). Image adapted from Google.

Gluthatione and cysteine are accountable for lipid metabolization. Without cysteine the cells will suffer gluthatione depletion, which is another very important metabolite, thus causing the lipids to oxidise and lead to cell death (9)(10).The genes SLC3A2 and SLC7A11 hold the code for the glutamate/cystine antiporter known as the Xc- or xCT transporter system (11) .  


Fig. 3 Is a visual presentation of the ferroptosis pathway. The Xcsystem is presented as the antiporter for gluthatione/cysteine. Image adopted from (12)

This antiporter will allow the cystine to pass through the cell wall. Inside the cell   the cystine will be metabolized to cysteine, yet another important metabolite for the cell survival. Without the cysteine the cell will undergo depletion of gluthatione and accumulate oxidized lipids. The way immunotherapy works is by activating the CD8+ T cells. These cells will release interferon gamma ( INFγ) which down regulates the expression of the genes mentioned above. This cycle of all these metabolites depending on each other is broken and the cell cannot survive, therefore the cell dies (13).

Conclusion – So far the immunotherapy has been effective on only 30%of the patients(14). This research has shed new light on different mechanisms within the body we can use to fight cancer. It is important to continue research on various ways to push the ferroptosis pathway forward so that immunotherapy gives higher results for cancer patients.

COPYRIGHT: This article is the property of We Speak Science, a non-profit institution co-founded by Dr. Detina Zalli and Dr. Argita Zalli. The article is written by  Arrita Beqa, University of Prishtina, Kosovo.

References:

  1. https://www.sciencedaily.com/releases/2016/11/161115083915.htm
  2. Yang WS, Stockwell BR (March 2016). “Ferroptosis: Death by Lipid Peroxidation”Trends in Cell Biology26 (3): 165–176. doi:10.1016/j.tcb.2015.10.014PMC 4764384PMID 26653790.
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378329/#B1
  4. Banach M, Juranek JK, Zygulska AL (2017) Chemotherapy-induced neuropathies: a growing problem for patients and health care providers. Brain Behav 7:e00558. 10.1002/brb3.558,https://www.ncbi.nlm.nih.gov/pubmed/28127506
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  8. Golstein, P. & Griffiths, G. M. An early history of T cell-mediated cytotoxicity. Nat. Rev. Immunol. 18, 527–535 (2018), https://www.nature.com/articles/s41577-018-0009-3
  9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887533/
  10. https://www.ncbi.nlm.nih.gov/pubmed/28204974
  11. https://www.nature.com/articles/s41586-019-1170-y#ref-CR4
  12. https://www.tocris.com/cell-biology/ferroptosis
  13. https://www.nature.com/articles/s41586-019-1170-y#ref-CR4
  14. https://www.sciencedaily.com/releases/2019/05/190501131413.htm