An increase in glucosylceramide synthase induces Bcl-xL-mediated cell survival in vinorelbine-resistant lung adenocarcinoma cells

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// Wei-Hsin Chiu 1 , Wu-Chou Su 1 , Chia-Ling Li 1 , Chia-Ling Chen 2 and Chiou-Feng Lin 3,4 1 Division of Hemato-Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan 2 Center for Translational Medicine, Taipei Medical University, Taipei, Taiwan 3 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan 4 Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan Correspondence to: Chia-Ling Chen, email: // Chiou-Feng Lin, email: // Keywords : glucosylceramide synthase, vinorelbine, Bcl-xL, lung cancer, multiple drug-resistances Received : January 08, 2015 Accepted : April 23, 2015 Published : May 12, 2015 Abstract Reversing drug resistance with concurrent treatment confers anticancer benefits. In this study, we investigated the potential mechanism of glucosylceramide synthase (GCS)-mediated vinca alkaloid vinorelbine (VNR) resistance in human lung adenocarcinoma cells. Compared with PC14PE6/AS2 (AS2) and CL1-0 cells, apoptotic analysis showed that both A549 and CL1-5 cells were VNR-resistant, while these cells highly expressed GCS at the protein level. VNR treatment significantly converts ceramide to glucosylceramide in VNR-resistant cells; however, pharmacologically inhibiting GCS with (±)- threo -1-Phenyl-2-decanoylamino-3-morpholino-1-propanol hydrochloride (PDMP) induced ceramide accumulation, accompanied by a decrease in glucosylceramide. Under concurrent treatment with VNR and PDMP, an increase in cell apoptosis could be identified; furthermore, genetically silencing GCS confirmed these effects. In VNR-resistant cells, Bcl-xL expression was aberrantly increased, while pharmacologically inhibiting Bcl-xL with ABT-737 sensitized cells to VNR-induced apoptosis. Conversely, enforced expression of Bcl-xL strengthened the survival response of the VNR-susceptible cells AS2 and CL1-0. Without changes in mRNA expression, Bcl-xL was overexpressed independent of β-catenin-mediated transcriptional regulation in VNR-resistant cells. Simultaneous GCS inhibition and VNR treatment caused a decrease in Bcl-xL expression. According to these findings, an increase in GCS caused Bcl-xL augmentation, facilitating VNR resistance in lung adenocarcinoma cells.