Document Detail

Different modes of internalization of apoptotic alkyl-lysophospholipid and cell-rescuing lysophosphatidylcholine.
MedLine Citation:
PMID:  12837133     Owner:  NLM     Status:  MEDLINE    
The synthetic alkyl-lysophospholipid (ALP), Et-18-OCH3 (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine), can induce apoptosis in tumour cells. Unlike conventional chemotherapeutic drugs, ALP acts at the cell-membrane level. We have reported previously that ALP is internalized, and interferes with phosphatidylcholine (PC) biosynthesis de novo, which appeared to be essential for survival in lymphoma cells [Van der Luit, Budde, Ruurs, Verheij and Van Blitterswijk (2002) J. Biol. Chem. 277, 39541-39547]. Here, we report that, in HeLa cells, ALP accumulates in lipid rafts, and that internalization is inhibited by low temperature, monensin, disruption of lipid rafts and expression of a dominant-negative mutant of dynamin bearing a replacement of Lys44 with alanine (K44A). Thus ALP is internalized via raft- and dynamin-mediated endocytosis. Dynamin-K44A alleviated the ALP-induced inhibition of PC synthesis and rescued the cells from apoptosis induction. Additional cell rescue was attained by exogenous lysoPC, which after internalization serves as an alternative substrate for PC synthesis (through acylation). Unlike ALP, and despite the high structural similarity to ALP, lysoPC uptake did not occur via lipid rafts and did not depend on functional dynamin, indicating no involvement of endocytosis. Albumin back-extraction experiments suggested that (radiolabelled) lysoPC undergoes transbilayer movement (flipping). We conclude that ALP is internalized by endocytosis via lipid rafts to cause apoptosis, while exogenous cell-rescuing lysoPC traverses the plasma membrane outside rafts by flipping. Additionally, our data imply the importance of ether bonds in lyso-phospholipids, such as in ALP, for partitioning in lipid rafts.
Arnold H Van Der Luit; Marianne Budde; Marcel Verheij; Wim J Van Blitterswijk
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Biochemical journal     Volume:  374     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2003-09-04     Completed Date:  2003-09-30     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  747-53     Citation Subset:  IM    
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, NL-1066 CX Amsterdam, The Netherlands.
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MeSH Terms
Antigens, CD / metabolism
Apoptosis* / drug effects
Boron Compounds / metabolism
DNA Fragmentation / drug effects
Dynamins / metabolism,  physiology
Flow Cytometry / methods
Hela Cells
Lactosylceramides / metabolism
Lysophosphatidylcholines / chemistry,  metabolism*
Lysophospholipids / antagonists & inhibitors,  chemistry*
Membrane Microdomains / chemistry,  metabolism
Phosphatidylcholines / biosynthesis,  metabolism
Tumor Cells, Cultured
Reg. No./Substance:
0/4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; 0/Antigens, CD; 0/Boron Compounds; 0/Lactosylceramides; 0/Lysophosphatidylcholines; 0/Lysophospholipids; 0/Phosphatidylcholines; 10028-17-8/Tritium; 4682-48-8/CDw17 antigen; EC

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