Mechanisms of Ferroptosis Evasion Promoted by Extracellular Metabolites
Abstract/Contents
- Abstract
- Cancer cells require nutrients to grow and proliferate. The availability of the amino acid cysteine impacts whether cancer cells die by an iron-dependent, non-apoptotic form of cell death executed by lipid peroxidation called ferroptosis. Ferroptosis can be induced if the availability of the amino acid cysteine is limiting or by inhibiting the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). Extracellular metabolites such as monounsaturated fatty acids (MUFAs) and cysteine can protect from ferroptosis. However, it is unclear how cancer cells acquire cysteine to evade ferroptosis or what MUFAs they can use to evade ferroptosis. Using human-derived cancer cell lines in both adherent (2D) and suspension (3D) culture, this study demonstrates that the cysteine-rich extracellular protein albumin protects from ferroptosis caused by cysteine deprivation. Albumin in combination with inhibition of the nutrient and energy sensing kinase, mammalian target of rapamycin complex 1 (mTORC1), is required to robustly protect from cysteine deprivation-induced ferroptosis in 2D. This combination treatment protects from ferroptosis by increasing intracellular levels of cysteine. Furthermore, this process is dependent on the catabolism of albumin into its amino acid constituents. Additionally, albumin protects from cystine deprivation-induced ferroptosis in 3D culture. This study reveals that a variety of exogenous MUFAs that have not previously been characterized as ferroptosis-protective metabolites protect HT-1080 cells in monolayer and HT-1080 and Panc-1 spheroids from GPX4 inhibition-induced ferroptosis. These MUFAs exhibit different protective abilities in adherent compared to spheroid culture and this suggests growth-context dependent differences in MUFA protection. These results describe novel metabolite-mediated strategies of ferroptosis evasion in 2D and 3D culture. Understanding how cells utilize exogenous protective metabolites such as albumin and MUFAs in death-inducing conditions can reveal novel ways to induce more complete cancer cell death by curtailing alternative avenues of protection. Targeting these mechanisms to induce more effective cell death in cancer cells reveals potential therapeutic relevance of this work.
Description
| Type of resource | text |
|---|---|
| Publication date | May 4, 2023 |
Creators/Contributors
| Author | Alchemy, Grace |
https://orcid.org/0000-0002-2173-8878
(unverified)
|
|---|---|---|
| Thesis advisor | Dixon, Scott |
https://orcid.org/0000-0001-6230-8199
(unverified)
|
| Thesis advisor | Gozani, Or |
https://orcid.org/0000-0002-1365-4463
(unverified)
|
| Degree granting institution | Stanford University, Department of Biology |
Subjects
| Subject | Ferroptosis |
|---|---|
| Subject | Cysteine |
| Subject | Albumin |
| Subject | Lysosome |
| Subject | Monounsaturated Fatty Acids |
| Subject | Spheroid |
| Subject | Biology |
| Genre | Text |
| Genre | Thesis |
Bibliographic information
| Related item | |
|---|---|
| DOI | https://doi.org/10.25740/wz120rw5803 |
| Location | https://purl.stanford.edu/wz120rw5803 |
Access conditions
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 4.0 International license (CC BY-NC).
Preferred citation
- Preferred citation
- Alchemy, G. and Dixon, S. (2024). Mechanisms of Ferroptosis Evasion Promoted by Extracellular Metabolites. Stanford Digital Repository. Available at https://purl.stanford.edu/wz120rw5803. https://doi.org/10.25740/wz120rw5803.
Collection
Undergraduate Theses, Department of Biology, 2022-2023
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- Contact
- alchemy@stanford.edu
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