Abstract
BackgroundResistance to chemotherapy drugs (e.g. taxol) has been a major obstacle in successful cancer treatment. In A549 human lung adenocarcinoma, acquired resistance to the first-line chemotherapy taxol has been a critical problem in clinics. Sphingolipid (SPL) controls various aspects of cell growth, survival, adhesion, and motility in cancer, and has been gradually regarded as a key factor in drug resistance. To better understand the taxol-resistant mechanism, a comprehensive sphingolipidomic approach was carried out to investigate the sphingolipid metabolism in taxol-resistant strain of A549 cell (A549T).MethodsA549 and A549T cells were extracted according to the procedure with optimal condition for SPLs. Sphingolipidomic analysis was carried out by using an UHPLC coupled with quadrupole time-of-flight (Q-TOF) MS system for qualitative profiling and an UHPLC coupled with triple quadrupole (QQQ) MS system for quantitative analysis. The differentially expressed sphingolipids between taxol-sensitive and -resistant cells were explored by using multivariate analysis.ResultsBased on accurate mass and characteristic fragment ions, 114 SPLs, including 4 new species, were clearly identified. Under the multiple reaction monitoring (MRM) mode of QQQ MS, 75 SPLs were further quantified in both A549 and A549T. Multivariate analysis explored that the levels of 57 sphingolipids significantly altered in A549T comparing to those of A549 (p < 0.001 and VIP > 1), including 35 sphingomyelins (SMs), 14 ceramides (Cers), 3 hexosylceramides (HexCers), 4 lactosylceramides (LacCers) and 1 sphingosine. A significant decrease of SM and Cer levels and overall increase of HexCer and LacCer represent the major SPL metabolic characteristic in A549T.ConclusionsThis study investigated sphingolipid profiles in human lung adenocarcinoma cell lines, which is the most comprehensive sphingolipidomic analysis of A549 and A549T. To some extent, the mechanism of taxol-resistance could be attributed to the aberrant sphingolipid metabolism, “inhibition of the de novo synthesis pathway” and “activation of glycosphingolipid pathway” may play the dominant role for taxol-resistance in A549T. This study provides insights into the strategy for clinical diagnosis and treatment of taxol resistant lung cancer.
Highlights
Resistance to chemotherapy drugs has been a major obstacle in successful cancer treatment
114 SPLs have been identified in the QC samples, among which Cer (d18:2/ 26:2), DHCer (d18:0/24:2), phytosphingosine (PTSo) t19:2, and PTSo t16:1 were new SPLs
Inhibition of sphingosine kinase 2 (SphK2) can enhance the apoptosis of non-small cell lung cancer (NSCLC) cells, and it will certainly result in an increase of the substrate sphingosine
Summary
Resistance to chemotherapy drugs (e.g. taxol) has been a major obstacle in successful cancer treatment. To better understand the taxol-resistant mechanism, a comprehensive sphingolipidomic approach was carried out to investigate the sphingolipid metabolism in taxol-resistant strain of A549 cell (A549T). Paclitaxel (taxol) is commonly used as part of combination chemotherapy for the treatment of non-small cell lung cancer including adenocarcinoma A549. It has been recognized that the dysregulated metabolic profile of cancer is linked to the chemoresistance [4] Cancer cells reprogram their metabolism to satisfy the demands of malignant phenotype, which decrease drug-induced apoptosis, conferring therapeutic resistance [5]. Since cellular SPLs appear to play a significant role in relation to cancer, their dysregulated synthesis and metabolism in drug-resistant cancer cells have been systematically studied [6]. The integrated LC-MS approach was employed to investigate the taxol resistance mechanism of A549T from the viewpoint of sphingolipidomic
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