Document Detail


Translocation of Fas by LPA prevents ovarian cancer cells from anti-Fas-induced apoptosis.
MedLine Citation:
PMID:  15661236     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: Alterations in the expression of Fas have been demonstrated in various cancers as a mechanism for tumor cells to escape from immune surveillance. In this study, we observed the effect of lysophosphatidic acid (LPA) on Fas expression and function in ovarian cancer cells. METHODS: Ovarian cancer cell lines were incubated with or without LPA and Fas cell surface presentations were detected by flow cytometry. Anti-Fas IgM was added for induction and analysis of apoptosis by flow cytometry. Cell lysis and subcellular fractions were probed for protein expression by Western blot. Cells were also stained with human anti-Fas Ab, followed with Rhodamine red-X-conjugated goat anti-mouse IgG, and immunofluorescence images were acquired on a Nikon digital camera. RESULTS: Following treatment with LPA, ovarian cancer cells showed significant rapid reduction of Fas presentation on the cell surface. LPA protected ovarian cancer cells from anti-Fas-induced apoptosis. Cell lysis and subcellular fractionations proved that LPA treatment induced a translocation of Fas receptors, along with phosphorylated ezrin, from the membrane anchored to the actin cytoskeleton, to the cytosol. Translocation of the Fas receptor reduced Fas concentration in the membrane and may inhibit its clustering and internalization during early apoptosis induced by anti-Fas. DISC staining proved that LPA inhibited Fas receptor aggregation and caspase-8 activation at the membrane, which further inhibited caspase-3 and 7 activation in the cytosol. CONCLUSIONS: Our studies suggest that LPA induces translocation of Fas from the cell membrane to the cytosol, which may provide a mechanism by which ovarian cancer cells evade FasL-bearing immune cells.
Authors:
Yuru Meng; Shijun Kang; John So; Scott Reierstad; David A Fishman
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Gynecologic oncology     Volume:  96     ISSN:  0090-8258     ISO Abbreviation:  Gynecol. Oncol.     Publication Date:  2005 Feb 
Date Detail:
Created Date:  2005-01-21     Completed Date:  2005-03-03     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0365304     Medline TA:  Gynecol Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  462-9     Citation Subset:  IM    
Affiliation:
Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY 10016, USA.
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MeSH Terms
Descriptor/Qualifier:
Antigens, CD95 / immunology,  metabolism*,  physiology
Apoptosis / drug effects*,  physiology
Caspases / metabolism
Cell Membrane / metabolism
Cell Movement / physiology
Cytosol / metabolism
Down-Regulation / drug effects
Enzyme Activation
Fas Ligand Protein
Female
Humans
Immunoglobulin M / immunology,  pharmacology
Lysophospholipids / pharmacology*
Membrane Glycoproteins / immunology,  metabolism,  physiology
Neoplasm Invasiveness
Ovarian Neoplasms / drug therapy*,  immunology,  metabolism*,  pathology
Grant Support
ID/Acronym/Agency:
P50 CA 836539/CA/NCI NIH HHS; R01 CA 01015/CA/NCI NIH HHS; R01 CA 82562/CA/NCI NIH HHS; R01 CA 89503/CA/NCI NIH HHS; U01 CA 85133/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD95; 0/FASLG protein, human; 0/Fas Ligand Protein; 0/Fasl protein, mouse; 0/Immunoglobulin M; 0/Lysophospholipids; 0/Membrane Glycoproteins; 22002-87-5/lysophosphatidic acid; EC 3.4.22.-/Caspases

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