Regulation of the new coexpressed CD55 (decay-accelerating factor) receptor on stomach carcinoma cells involved in antibody SC-1-induced apoptosis.
The human monoclonal antibody SC-1 was isolated from a patient with a diffuse-type adenocarcinoma of the stomach using somatic cell hybridization. The immunoglobulin (Ig)M antibody reacts specifically with diffuse- (70%) and intestinal-type (25%) gastric adenocarcinoma and induces apoptosis in vitro and in vivo. When used in clinical trials with stomach carcinoma patients, significant apoptotic and regressive effects in primary tumors have been observed with the antibody SC-1. The SC-1 receptor is a new 82 kd membrane-bound isoform of glycosylphosphatidylinositol (GPI)-linked CD55 (decay-accelerating factor, DAF). CD55 is known to protect cells from lysis through autologous complement and is coexpressed with the ubiquitously distributed 70 kd isoform. The SC-1-specific CD55 isoform is up-regulated shortly after antibody binding, followed by an internalization of the antibody/receptor-complex, whereas the membranous expression of wild-type CD55 remains unchanged. The apoptotic process is marked by cleavage of cytokeratin 18, indicating the involvement of caspase-6 in the apoptotic process. In contrast to other apoptotic pathways, a cleavage of poly(ADP-ribose)polymerase (PARP) is not observed. The expression of the cell-cycle regulator c-myc becomes up-regulated, whereas expression of topoisomerase IIalpha is down-regulated. Induction of apoptosis leads to an increase in the internal Ca(2+) concentration, which is not necessary for the apoptotic process but for the transport of newly synthesized SC-1-specific CD55 isoform to the membrane.
Hensel
F
F
Institute for PathologyUniversity of Würzburg, Würzburg, Germany.
Hermann
R
R
Brändlein
S
S
Krenn
V
V
Schmausser
B
B
Geis
S
S
Müller-Hermelink
H K
HK
Vollmers
H P
HP
D000230:Adenocarcinoma; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000276:immunology*; D018958:CD55 Antigens / Q000032:analysis / Q000096:biosynthesis* / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D053178:Caspase 6; D061945:Caspase Inhibitors; D002462:Cell Membrane / Q000502:physiology; D003593:Cytoplasm / Q000502:physiology; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D007633:Keratins / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013274:Stomach Neoplasms
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018958:CD55 Antigens; D061945:Caspase Inhibitors; C111124:SC-1 monoclonal antibody; D007633:Keratins; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505514:CASP6 protein, human; D053148:Caspase 3; D053178:Caspase 6; D002118:Calcium