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Untargeted Lipidomics Highlight the Depletion of Deoxyceramides during Therapy-Induced Senescence
Alec Millner1, Darleny Y Lizardo1, Gunes Ekin Atilla-Gokcumen1
1Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, NY, 14260, USA.
Abstract:
Therapy-induced senescence is a state of cell cycle arrest that occurs as a response to various chemotherapeutic reagents, especially ones that cause DNA damage. Senescent cells display resistance to cell death and can impair the efficacy of chemotherapeutic strategies. Since lipids can exhibit pro-survival activity, it is envisioned in this article that probing the lipidome could provide insights into novel lipids that are involved in senescence. Therefore, a tissue culture model system is established and the cellular lipidomes of senescent and proliferating cells are comparatively analyzed. Out of thousands of features detected, 17 species are identified that show significant changes in senescent cells. The majority of these species (11 out of 17) are atypical sphingolipids, 1-deoxyceramides/dihydroceramides, which are produced as a result of the utilization of alanine, instead of serine during sphingolipid biosynthesis. These lipids are depleted in senescent cells. Elevating the levels of deoxyceramides by supplementing the growth medium with metabolic precursors or by directly adding deoxyceramide result in decreased senescence, suggesting that these species might play a key role in this process.
Insights
Therapy-induced senescence involves cell cycle arrest and resistance to death. This study identifies depleted 1-deoxyceramides in senescent cells, suggesting they play a key role in this process.
Area of Science:
- Cell Biology
- Biochemistry
- Cancer Research
Background:
- Therapy-induced senescence is a cell cycle arrest triggered by chemotherapy, leading to treatment resistance.
- Senescent cells resist death, potentially hindering chemotherapeutic efficacy.
- Lipids may influence cell survival and senescence, warranting investigation of the lipidome.
Purpose of the Study:
- To investigate the role of lipids in therapy-induced senescence.
- To identify specific lipid species altered during senescence.
- To explore the functional significance of identified lipids in senescence.
Main Methods:
- Established a tissue culture model for therapy-induced senescence.
- Performed comparative analysis of cellular lipidomes in senescent versus proliferating cells.
- Utilized mass spectrometry to identify and quantify lipid species.
Main Results:
- Identified 17 lipid species with significant changes in senescent cells.
- Found that 11 of these species were atypical sphingolipids, specifically 1-deoxyceramides/dihydroceramides.
- Observed depletion of 1-deoxyceramides in senescent cells.
Conclusions:
- 1-deoxyceramides are significantly depleted in therapy-induced senescent cells.
- Supplementation with 1-deoxyceramides or their precursors reduces senescence.
- These atypical sphingolipids play a crucial role in regulating senescence.
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