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Comparative sphingolipidomic analysis reveals significant differences between doxorubicin-sensitive and -resistance
Ola D A Shammout1,2, Naglaa S Ashmawy2,3,4, Sarra B Shakartalla2,5,6
1College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.
Plos One
|October 12, 2021
Summary
Altered sphingolipids (SPLs) metabolism, particularly reduced ceramides and increased sphingomyelin, contributes to doxorubicin resistance in MCF-7 cells. This highlights potential therapeutic targets for overcoming drug resistance in cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Drug resistance is a major challenge in cancer therapy, leading to treatment failure.
- Alterations in sphingolipids (SPLs) have been linked to the development of drug resistance.
- Understanding these associations can reveal new therapeutic strategies.
Purpose of the Study:
- To investigate the role of sphingolipid metabolism in doxorubicin (dox)-resistance in MCF-7 breast cancer cells.
- To compare sphingolipid profiles between doxorubicin-sensitive and -resistant cell lines.
- To identify specific sphingolipids and metabolic pathways involved in doxorubicin resistance.
Main Methods:
- Comparative sphingolipidomics analysis of parental (dox-sensitive) and doxorubicin-resistant MCF-7 cell lines.
- Identification and quantification of 31 sphingolipids across 5 subcategories.
- Validation of sphingolipid alterations using gene expression analysis.
Main Results:
- Sphingolipid profiles clearly differentiated parental from doxorubicin-resistant cells.
- Eight specific sphingolipids, including various sphingomyelins (SM) and one hexosylceramide (HexCer), were significantly altered in resistant cells.
- Doxorubicin resistance was associated with decreased ceramide (Cer) levels and increased sphingomyelin (SM) levels.
- Gene expression data indicated activation of SM-Cer and GluCer-LacCer-ganglioside pathways, potentially promoting resistance to ceramide-induced apoptosis.
Conclusions:
- This study provides the first conclusive evidence linking dysregulated sphingolipid metabolism to doxorubicin resistance in MCF-7 cells.
- Sphingolipid metabolism in resistant cells shifts towards reduced ceramides and increased sphingomyelins.
- Altered enzymes in sphingolipid metabolism pathways represent potential therapeutic targets for overcoming doxorubicin resistance in breast cancer.
