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

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

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6 Citations (Scopus)

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 VNRinduced 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.

Original languageEnglish
Pages (from-to)20513-20524
Number of pages12
JournalOncotarget
Volume6
Issue number24
Publication statusPublished - 2015

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Keywords

  • Bcl-xL
  • Glucosylceramide synthase
  • Lung cancer
  • Multiple drug-resistances
  • Vinorelbine

ASJC Scopus subject areas

  • Oncology

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