Production and pro-apoptotic activity of soluble CD95 ligand in pancreatic carcinoma.
We report here that the progression of pancreatic carcinomas in tumor patients is associated with increased serum levels of both the soluble forms of CD95 ligand (CD95L/FasL) and its receptor, CD95 (Fas). Shedding of proteolytically processed soluble CD95L was also observed in pancreatic carcinoma cells in vitro, thus identifying one possible source of CD95L in patients' sera. Because the secreted forms of both CD95 and CD95L have been implicated previously in protection of cells from CD95-mediated cell death, we assessed the effect of soluble CD95L in supernatants of pancreatic carcinoma cells on viability of Jurkat T lymphocytes. We describe that (a) supernatants derived from cultured pancreatic carcinoma cells caused apoptosis of Jurkat cells; (b) soluble tumor-derived CD95L contributed significantly to this effect; and (c) in comparison to Jurkat cells, pancreatic carcinoma cells themselves revealed increased resistance to apoptosis induction by autocrine soluble CD95L. These results are consistent with the notion that in the microenvironment of pancreatic tumors, tumor-derived shed CD95L exerts paracrine pro-apoptotic effects. In addition, because it is released at high levels into the bloodstream, soluble CD95L may have systemic effects in tumor patients that reach beyond the microenvironment of the tumor site.
Bellone
G
G
Department of Clinical Physiopathology, University of Torino, Italy. bellone@golgi.molinette.unito.it
Smirne
C
C
Carbone
A
A
Mareschi
K
K
Dughera
L
L
Farina
E C
EC
Alabiso
O
O
Valente
G
G
Emanuelli
G
G
Rodeck
U
U
D000328:Adult; D000368:Aged; D017209:Apoptosis; D002277:Carcinoma / Q000097:blood / Q000378:metabolism*; D002469:Cell Separation; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D019169:Jurkat Cells; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000097:blood; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000097:blood / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000096:biosynthesis* / Q000097:blood
D017077:Culture Media, Conditioned; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D019014:fas Receptor; D049452:Green Fluorescent Proteins