Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism
Aneuploidy, or having a disrupted genome, is an aberration commonly found in tumours but rare in normal tissues. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift, which makes these cells sensitive to internal and environmental stresses. Using <i>Drosophila</i&g...
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MDPI AG
2023-05-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/13/5/642 |
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| author | Anowarul Islam Zeeshan Shaukat David L. Newman Rashid Hussain Michael G. Ricos Leanne Dibbens Stephen L. Gregory |
| author_facet | Anowarul Islam Zeeshan Shaukat David L. Newman Rashid Hussain Michael G. Ricos Leanne Dibbens Stephen L. Gregory |
| author_sort | Anowarul Islam |
| collection | DOAJ |
| description | Aneuploidy, or having a disrupted genome, is an aberration commonly found in tumours but rare in normal tissues. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift, which makes these cells sensitive to internal and environmental stresses. Using <i>Drosophila</i> as a model, we investigated the changes in transcription in response to ongoing changes to ploidy (chromosomal instability, CIN). We noticed changes in genes affecting one-carbon metabolism, specifically those affecting the production and use of s-adenosyl methionine (SAM). The depletion of several of these genes has led to cell death by apoptosis in CIN cells but not in normal proliferating cells. We found that CIN cells are particularly sensitive to SAM metabolism at least partly because of its role in generating polyamines. Feeding animals spermine was seen to rescue the cell death caused by the loss of SAM synthase in CIN tissues. The loss of polyamines led to decreased rates of autophagy and sensitivity to reactive oxygen species (ROS), which we have shown to contribute significantly to cell death in CIN cells. These findings suggest that a well-tolerated metabolic intervention such as polyamine inhibition has the potential to target CIN tumours via a relatively well-characterised mechanism. |
| first_indexed | 2024-03-11T03:30:14Z |
| format | Article |
| id | doaj.art-4238da4def2946f3a9541570b02f4c76 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-11T03:30:14Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-4238da4def2946f3a9541570b02f4c762023-11-18T02:25:45ZengMDPI AGMetabolites2218-19892023-05-0113564210.3390/metabo13050642Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon MetabolismAnowarul Islam0Zeeshan Shaukat1David L. Newman2Rashid Hussain3Michael G. Ricos4Leanne Dibbens5Stephen L. Gregory6College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia 2 Clinical and Health Sciences, University of South Australia, Adelaide 5001, Australia 3 School of Biological Sciences, University of Adelaide, Adelaide 5006, AustraliaClinical and Health Sciences, University of South Australia, Adelaide 5001, AustraliaSchool of Biological Sciences, University of Adelaide, Adelaide 5006, AustraliaClinical and Health Sciences, University of South Australia, Adelaide 5001, AustraliaClinical and Health Sciences, University of South Australia, Adelaide 5001, AustraliaClinical and Health Sciences, University of South Australia, Adelaide 5001, AustraliaCollege of Medicine and Public Health, Flinders University, Adelaide 5042, Australia 2 Clinical and Health Sciences, University of South Australia, Adelaide 5001, Australia 3 School of Biological Sciences, University of Adelaide, Adelaide 5006, AustraliaAneuploidy, or having a disrupted genome, is an aberration commonly found in tumours but rare in normal tissues. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift, which makes these cells sensitive to internal and environmental stresses. Using <i>Drosophila</i> as a model, we investigated the changes in transcription in response to ongoing changes to ploidy (chromosomal instability, CIN). We noticed changes in genes affecting one-carbon metabolism, specifically those affecting the production and use of s-adenosyl methionine (SAM). The depletion of several of these genes has led to cell death by apoptosis in CIN cells but not in normal proliferating cells. We found that CIN cells are particularly sensitive to SAM metabolism at least partly because of its role in generating polyamines. Feeding animals spermine was seen to rescue the cell death caused by the loss of SAM synthase in CIN tissues. The loss of polyamines led to decreased rates of autophagy and sensitivity to reactive oxygen species (ROS), which we have shown to contribute significantly to cell death in CIN cells. These findings suggest that a well-tolerated metabolic intervention such as polyamine inhibition has the potential to target CIN tumours via a relatively well-characterised mechanism.https://www.mdpi.com/2218-1989/13/5/642s-adenosyl methioninesperminegenomic instabilityreactive oxygen species (ROS)<i>Drosophila</i>autophagy |
| spellingShingle | Anowarul Islam Zeeshan Shaukat David L. Newman Rashid Hussain Michael G. Ricos Leanne Dibbens Stephen L. Gregory Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism Metabolites s-adenosyl methionine spermine genomic instability reactive oxygen species (ROS) <i>Drosophila</i> autophagy |
| title | Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism |
| title_full | Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism |
| title_fullStr | Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism |
| title_full_unstemmed | Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism |
| title_short | Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism |
| title_sort | chromosomal instability causes sensitivity to polyamines and one carbon metabolism |
| topic | s-adenosyl methionine spermine genomic instability reactive oxygen species (ROS) <i>Drosophila</i> autophagy |
| url | https://www.mdpi.com/2218-1989/13/5/642 |
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