Tumor Biology

, Volume 37, Issue 5, pp 6205–6216 | Cite as

The alkyllysophospholipid edelfosine enhances TRAIL-mediated apoptosis in gastric cancer cells through death receptor 5 and the mitochondrial pathway

  • Sung-Chul Lim
  • Keshab Raj Parajuli
  • Song Iy Han
Original Article

Abstract

The ether phospholipid edelfosine is the prototype of a group of synthetic antitumor alkyllysophospholipid (ALP) compounds that exert pro-apoptotic effects in various types of cancer cells through cell type-dependent mechanisms. In this study, we examined the antitumor effect of edelfosine in human gastric cancer cells. Edelfosine decreased cell viability and induced autophagic death at a moderate concentration (~30 μM), whereas it induced apoptotic cell death at concentrations over 30 μM. Interestingly, low concentrations of edelfosine (5–10 μM) effectively enhanced recombinant human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (rhTRAIL/TNFSF10)-induced apoptosis and clonogenicity in gastric cancer cells, including TRAIL-resistant AGS cells. Edelfosine upregulated the protein level of death receptor 5 (DR5/TNFRSF10B) and/or increased DR5 upregulation in lipid rafts. In addition, edelfosine-mediated rhTRAIL sensitization was regulated by the DR5 pathway. Edelfosine also activated p38MAPK (MAPK14), and edelfosine-mediated rhTRAIL sensitization was partially regulated by a p38-mediated decrease in mitochondrial membrane potential. This study suggests a novel therapeutic strategy targeting gastric cancer cells by using the combination of edelfosine and TRAIL.

Keywords

Edelfosine Alkyllysophospholipid Gastric cancer TRAIL Apoptosis 

Notes

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2013R1A1A3013127). We thank Prof. Tae-Hyoung Kim for the kind gift of rhTRAIL and Ms. Jeong-Eun Choi for her excellent technical assistance.

Supplementary material

13277_2015_4485_Fig7_ESM.gif (16 kb)
Supplementary Figure 1

(A) SNU601 cells were incubated with 0, 1, 2.5, 5, 7.5, 10, 15, 20 nM bafilomycin A1 for 48 h and MTT assay were performed. (B) SNU601 cells were incubated with 0, 1, 2.5, 5, 7.5, 10, 15, 20 nM bafilomycin A1 for 48 h in the presence of 2 μM rapamycin, and autophagy was determined by MDC staining and fluorescence microscopy. (GIF 16 kb)

13277_2015_4485_MOESM1_ESM.tif (2.4 mb)
High resolution image (TIF 2410 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Sung-Chul Lim
    • 1
    • 2
  • Keshab Raj Parajuli
    • 2
  • Song Iy Han
    • 2
    • 3
  1. 1.Department of Pathology, College of MedicineChosun UniversityGwangjuKorea
  2. 2.Research Center for Resistant CellsChosun UniversityGwangjuKorea
  3. 3.Division of Premedical Science, College of MedicineChosun UniversityGwangjuKorea

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