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

Wei-Hsin Chiu; Wu-Chou Su; Chia-Ling Li; Chia-Ling Chen; Chiou-Feng Lin

doi:10.18632/oncotarget.4109

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Research Papers:

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

Wei-Hsin Chiu, Wu-Chou Su, Chia-Ling Li, Chia-Ling Chen and Chiou-Feng Lin _

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Oncotarget. 2015; 6:20513-20524. https://doi.org/10.18632/oncotarget.4109

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Abstract

Wei-Hsin Chiu1, Wu-Chou Su1, Chia-Ling Li1, Chia-Ling Chen2 and Chiou-Feng Lin3,4

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.

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Research Papers:

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

Abstract