On the mechanism of alkylphosphocholine (APC)-induced apoptosis in tumour cells.
Alkylphosphocholines (APCs) represent a new and very encouraging class of antitumour agents that have also been shown to induce apoptosis in tumour cells, but their exact mode of action has still not been elucidated. The APC compound presented here, S-1-O-phosphocholine-2- N-acetyl-octadecane (S-NC-2) induces apoptosis in a variety of cancer cells. To define the molecular requirements for S-NC-2-induced apoptosis, activation of caspase-8 and -3 and the cleavage of death substrates, such as poly(ADP-ribose) polymerase (PARP), were investigated in Jurkat, BJAB, SKW6.4 and K562 cells. The signalling pathway seems to be initiated at the death receptor level. Cells that are defective in Fas-receptor signalling (e.g., FADDdn BJAB), as well as cells lacking the Fas receptor (K562), were resistant to S-NC-2 treatment. Furthermore, the treatment of Jurkat cells with S-NC-2 resulted in the clustering of death receptor molecules and co-localisation of the Fas receptor with caveolin, a marker for lipid rafts. In addition, the involvement of mitochondria was detected, since S-NC-2 induces the breakdown of the mitochondrial membrane potential. Overexpression of the anti-apoptotic protein Bcl-2 prevented the loss of delta psi(m) in type II (Jurkat) but not in type I cells (SKW6.4). Moreover, cleavage of Bid was found, which points to a possible linkage between the receptor-dependent and the mitochondrial pathways.
Oberle
Carolin
C
Forschungszentrum Karlsruhe GmbH, Institut für Toxikologie und Genetik, P.O. Box 3640, D-76021 Karlsruhe, Germany.
Massing
Ulrich
U
Krug
Harald F
HF
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
D019014:fas Receptor; D010767:Phosphorylcholine; D020169:Caspases