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.
Highlights
Sphingolipids (SPLs) are a kind of membrane and intracellular lipids that typically play structural roles and act as signaling molecules and/or modulators of signaling pathways associated with cell survival[8]
By integrating the high efficient separation offered by UHPLC, high-resolution mass spectrum obtained by MS and MS/MS on quadrupole time-of-flight (Q-TOF), as well as comparing the data with those of reference standards and searching against our personal database, totally 102 SPLs have been identified in the pooled samples, among which six ceramides (d18:1/17:3; d18:1/15:3(OH); d18:1/14:3(OH); d18:2/23:1; d18:0/18:3 and d17:0/13:0(OH)), two ceramide-1-phosphates (d18:1/19:0(OH) and d18:1/12:2), one hexosylceramide (d18:1/20:1), and three sphingosines (d16:3; d15:3 and t19:2) are new SPLs
Since the role of sphingolipids in cancer cell has been widely recognized, comprehensive sphingolipidomic study is essential for exploring its drug resistance mechanism
Summary
Sphingolipids (SPLs) are a kind of membrane and intracellular lipids that typically play structural roles and act as signaling molecules and/or modulators of signaling pathways associated with cell survival[8]. Qualitative and quantitative assessment of SPLs could reveal novel biomarkers for early diagnosis of cancer[13]. There are several studies focused on the sphingolipidomics of A2780 Human Ovarian Cancer cell line[14,15], as well as its fenretinide-resistant[16] and multidrug-resistant strains[17,18]. Valsecchi M et al have characterized the sphingolipidomes in N-(4-hydroxyphenyl)retinamide (4-HPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) treated A2780 cells by ESI-MS, revealed that the two drugs differentially affect the early steps of SPL synthesis[19]. Increasing evidence suggests the change of SPL metabolism can be (one of) the crucial mechanism of drug resistance in A2780 cells. A comprehensive sphingolipidomic study is required for elucidating the mechanisms underlying the resistance of A2780T cells to taxol treatment. It appears to be a promising tool for viewing overall sphingolipidomic difference between taxol-sensitive and -resistant strain of A2780
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