The ALP (alkyl-lysophospholipid) edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) induces apoptosis in S49 mouse lymphoma cells. A variant cell line, S49AR, made resistant to ALP, was found previously to be impaired in ALP uptake via lipid-raft-mediated endocytosis. In the present paper, we report that these cells display cross-resistance to Fas/CD95 ligation [FasL (Fas ligand)], and can be gradually resensitized by prolonged culturing in the absence of ALP. Fas and ALP activate distinct apoptotic pathways, since ALP-induced apoptosis was not abrogated by dominant-negative FADD (Fas-associated protein with death domain), cFLIPL [cellular FLICE (FADD-like interleukin 1β-converting enzyme)-inhibitory protein long form] or the caspase 8 inhibitor Z-IETD-FMK (benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethylketone). ALP-resistant cells showed decreased Fas expression, at both the mRNA and protein levels, in a proteasome-dependent fashion. The proteasome inhibitor MG132 partially restored Fas expression and resensitized the cells to FasL, but not to ALP. Resistant cells completely lacked SM (sphingomyelin) synthesis, which seems to be a unique feature of the S49 cell system, having very low SM levels in parental cells. Lack of SM synthesis did not affect cell growth in serum-containing medium, but retarded growth under serum-free (SM-free) conditions. SM deficiency determined in part the resistance to ALP and FasL. Exogenous short-chain (C12-) SM partially restored cell-surface expression of Fas in lipid rafts and FasL sensitivity, but did not affect Fas mRNA levels or ALP sensitivity. We conclude that the acquired resistance of S49 cells to ALP is associated with down-regulated SM synthesis and Fas gene transcription and that SM in lipid rafts stabilizes Fas expression at the cell surface.
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Research Article|
December 14 2009
Fas/CD95 down-regulation in lymphoma cells through acquired alkyllysophospholipid resistance: partial role of associated sphingomyelin deficiency
Wim J. van Blitterswijk;
Wim J. van Blitterswijk
1
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
1To whom correspondence should be addressed (email w.v.blitterswijk@nki.nl).
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Jeffrey B. Klarenbeek;
Jeffrey B. Klarenbeek
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Arnold H. van der Luit;
Arnold H. van der Luit
2
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Maaike C. Alderliesten;
Maaike C. Alderliesten
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Menno van Lummel;
Menno van Lummel
3
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Marcel Verheij
Marcel Verheij
†Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Publisher: Portland Press Ltd
Received:
March 19 2009
Revision Received:
October 12 2009
Accepted:
October 14 2009
Accepted Manuscript online:
October 14 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 425 (1): 225–236.
Article history
Received:
March 19 2009
Revision Received:
October 12 2009
Accepted:
October 14 2009
Accepted Manuscript online:
October 14 2009
Citation
Wim J. van Blitterswijk, Jeffrey B. Klarenbeek, Arnold H. van der Luit, Maaike C. Alderliesten, Menno van Lummel, Marcel Verheij; Fas/CD95 down-regulation in lymphoma cells through acquired alkyllysophospholipid resistance: partial role of associated sphingomyelin deficiency. Biochem J 1 January 2010; 425 (1): 225–236. doi: https://doi.org/10.1042/BJ20090455
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