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Enrichment for Chemoresistant Ovarian Cancer Stem Cells from Human Cell Lines
Published on: September 10, 2014
LC-MS Based Sphingolipidomic Study on A2780 Human Ovarian Cancer Cell Line and its Taxol-resistant Strain
Hao Huang1,2, Tian-Tian Tong1, Lee-Fong Yau1
1State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
Abstract:
Drug resistance elicited by cancer cells continue to cause huge problems world-wide, for example, tens of thousands of patients are suffering from taxol-resistant human ovarian cancer. However, its biochemical mechanisms remain unclear. Sphingolipid metabolic dysregulation has been increasingly regarded as one of the drug-resistant mechanisms for various cancers, which in turn provides potential targets for overcoming the resistance. In the current study, a well-established LC-MS based sphingolipidomic approach was applied to investigate the sphingolipid metabolism of A2780 and taxol-resistant A2780 (A2780T) human ovarian cancer cell lines. 102 sphingolipids (SPLs) were identified based on accurate mass and characteristic fragment ions, among which 12 species have not been reported previously. 89 were further quantitatively analyzed by using multiple reaction monitoring technique. Multivariate analysis revealed that the levels of 52 sphingolipids significantly altered in A2780T cells comparing to those of A2780 cells. These alterations revealed an overall increase of sphingomyelin levels and significant decrease of ceramides, hexosylceramides and lactosylceramides, which concomitantly indicated a deviated SPL metabolism in A2780T. This is the most comprehensive sphingolipidomic analysis of A2780 and A2780T, which investigated significantly changed sphingolipid profile in taxol-resistant cancer cells. The aberrant sphingolipid metabolism in A2780T could be one of the mechanisms of taxol-resistance.
Insights
Drug resistance in ovarian cancer is a major problem. This study reveals altered sphingolipid metabolism, with increased sphingomyelin and decreased ceramides, in taxol-resistant cells, offering new insights into resistance mechanisms.
Area of Science:
- Biochemistry
- Cancer Biology
- Metabolomics
Background:
- Drug resistance in cancer, particularly taxol-resistant ovarian cancer, poses significant clinical challenges.
- The underlying biochemical mechanisms of taxol resistance remain largely unclear.
- Sphingolipid metabolic dysregulation is emerging as a key factor in cancer drug resistance.
Purpose of the Study:
- To investigate the sphingolipid metabolism in taxol-sensitive (A2780) and taxol-resistant (A2780T) human ovarian cancer cell lines.
- To identify specific alterations in sphingolipid profiles associated with taxol resistance.
- To explore potential therapeutic targets for overcoming taxol resistance.
Main Methods:
- Utilized a liquid chromatography-mass spectrometry (LC-MS) based sphingolipidomic approach.
- Identified 102 sphingolipids (SPLs), including 12 novel species.
- Quantitatively analyzed 89 SPLs using multiple reaction monitoring (MRM).
Main Results:
- Significant alterations in 52 sphingolipids were observed in A2780T cells compared to A2780 cells.
- A notable increase in sphingomyelin levels was detected.
- A significant decrease in ceramides, hexosylceramides, and lactosylceramides was found, indicating deviated SPL metabolism.
Conclusions:
- The study presents the most comprehensive sphingolipidomic analysis of A2780 and A2780T cells to date.
- Aberrant sphingolipid metabolism, characterized by altered sphingomyelin and ceramide levels, is implicated in taxol resistance in ovarian cancer.
- These findings suggest sphingolipid metabolic pathways as potential targets for overcoming taxol resistance.
