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Updated: Jul 15, 2025
Techniques to Induce and Quantify Cellular Senescence
Published on: May 1, 2017
DNA damage-induced senescence is associated with metabolomic reprogramming in breast cancer cells
Neena George1, Manjunath B Joshi2, Kapaettu Satyamoorthy3
1Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576 104, India.
Abstract:
Senescence due to exogenous and endogenous stresses triggers metabolic reprogramming and is associated with many pathologies, including cancer. In solid tumors, senescence promotes tumorigenesis, facilitates relapse, and changes the outcomes of anti-cancer therapies. Hence, cellular and molecular mechanisms regulating senescent pathways make attractive therapeutic targets. Cancer cells undergo metabolic reprogramming to sustain the growth-arrested state of senescence. In the present study, we aimed to understand the metabolic reprogramming in MCF-7 breast tumor cells in response to two independent inducers of DNA damage-mediated senescence, including ionizing radiation and doxorubicin. Increased DNA double-strand breaks, as demonstrated by γH2AX staining, showed a senescence phenotype, with expression of senescence-associated β-galactosidase accompanied by the upregulation of p21 and p16 in both groups. Further, untargeted analysis of the senescence-related extracellular metabolome profile of MCF-7 cells showed significantly reduced concentrations of carnitine and pantothenic acid and increased levels of S-adenosylhomocysteine in doxorubicin-treated cells, indicating the accumulation of ROS mediated DNA damage and impaired mitochondrial membrane potential. Similarly, a significant decline in the creatine level was observed in radiation-exposed cells, suggesting an increase in oxidative stress-mediated DNA damage. Our study, therefore, provides key effectors of the metabolic changes in doxorubicin and radiation-induced early senescence in MCF-7 breast cancer cells.
Insights
Cellular senescence, triggered by DNA damage in breast cancer cells, alters metabolism. This study identifies key metabolic changes in MCF-7 cells treated with doxorubicin or radiation, offering therapeutic targets.
Area of Science:
- Oncology
- Cell Biology
- Metabolic Research
Background:
- Cellular senescence, a state of irreversible growth arrest, is induced by various stresses, including DNA damage.
- Senescence plays a complex role in cancer, influencing tumorigenesis, relapse, and treatment response.
- Metabolic reprogramming is crucial for cancer cells to maintain the senescent state.
Purpose of the Study:
- To investigate the metabolic reprogramming in MCF-7 breast tumor cells undergoing senescence induced by ionizing radiation and doxorubicin.
- To identify specific metabolic alterations associated with DNA damage-mediated senescence in breast cancer.
Main Methods:
- Induction of senescence in MCF-7 cells using ionizing radiation and doxorubicin.
- Assessment of senescence markers including γH2AX, senescence-associated β-galactosidase, p21, and p16.
- Untargeted extracellular metabolome profiling to analyze metabolic changes.
Main Results:
- Both treatments induced senescence, confirmed by increased DNA double-strand breaks and senescence markers.
- Doxorubicin treatment led to decreased carnitine and pantothenic acid and increased S-adenosylhomocysteine, suggesting ROS-mediated damage and impaired mitochondrial function.
- Ionizing radiation exposure resulted in decreased creatine levels, indicating increased oxidative stress.
Conclusions:
- Doxorubicin and ionizing radiation induce distinct metabolic reprogramming in early senescent MCF-7 breast cancer cells.
- Specific metabolites like carnitine, pantothenic acid, S-adenosylhomocysteine, and creatine are key effectors of metabolic changes during induced senescence.
- Understanding these metabolic shifts provides potential therapeutic targets for managing senescence in breast cancer.
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