The human IgM antibody SAM-6 induces tumor-specific apoptosis with oxidized low-density lipoprotein.
Lipids are essential for normal and malignant cells during growth and differentiation. The turnover is strictly regulated because an uncontrolled uptake and accumulation is cytotoxic and can lead to lipoapoptosis: lipoptosis. The human monoclonal antibody SAM-6 binds to a cell surface receptor on malignant cells and to oxidized low-density lipoprotein (LDL). SAM-6 induces an excess of intracellular lipids, by overfeeding malignant cells with oxidized LDL, via a receptor-mediated endocytosis. The treated cells overaccumulate depots of cholesteryl esters and triglycerides. This lipid overaccumulation is tumor specific; nonmalignant cells neither bind the antibody nor harvest lipids after incubation. Because for both forms of apoptosis, the death domain dependent ("extrinsic") and independent ("intrinsic"), the activation of proteases is crucial, we also investigated this pathway in more detail. It was found that shortly after internalization of antibody/oxidized LDL/receptor complex and formation of lipid depots, cytochrome c is released by mitochondria. Followed by this, initiator caspase-8 and caspase-9 and effector caspase-3 and caspase-6 are activated. The mechanism of mitochondrial trigger (e.g., by free fatty acids) is under investigation. However, the present data indicate that the SAM-6 antibody induces an intrinsic-like form of apoptosis by overfeeding malignant cells with lipoproteins.
Brändlein
Stephanie
S
Institute of Pathology, University of Würzburg, Würzburg, 97080 Germany.
Rauschert
Nicole
N
Rasche
Leo
L
Dreykluft
Angela
A
Hensel
Frank
F
Conzelmann
Ernst
E
Müller-Hermelink
Hans-Konrad
HK
Vollmers
H Peter
HP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007075:Immunoglobulin M / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000032:analysis; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000473:pathology*; D011485:Protein Binding
D000911:Antibodies, Monoclonal; D007075:Immunoglobulin M; D008055:Lipids; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D045304:Cytochromes c; D020169:Caspases