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

作者：Chiu Wei Hsin; Su Wu Chou; Li Chia Ling; Chen Chia Ling^*; Lin Chiou Feng

来源：Oncotarget, 2015, 6(24): 20513-20524.

DOI：10.18632/oncotarget.4109

• glucosylceramide synthase
• vinorelbine
• Bcl-xL
• lung cancer
• multiple drug-resistances

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 beta-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.

• 出版日期2015-8-21
• 单位河北医科大学