TP-110, a new proteasome inhibitor, down-regulates IAPs in human multiple myeloma cells.
TP-110, a new proteasome inhibitor, has previously shown potent growth inhibition in various tumor cell lines. In this study, the mechanism of TP-110-induced apoptosis is investigated in a human multiple myeloma cell line. Treatment with TP-110 for 24 h in vitro induced apoptosis in multiple myeloma cell line RPMI8226. Although the expression of Bcl-2, Bcl-xL and Bax was not affected by the treatment of TP-110, cleavage of Bid and release of cytochrome c were enhanced. Interestingly, TP-110 reduced the intrinsic inhibitor of apoptosis proteins (IAPs), cIAP-1 and XIAP, that suppress executioner caspases. The reduction of IAPs was observed not only by TP-110, but also by another proteasome inhibitor, MG-132. These results indicate that proteasome inhibitors reduce the level of IAPs and that the apoptosis induced by TP-110 is correlated with the level of IAPs in leukemia cell lines. Additionally, a reduction of cIAP-1 and XIAP by TP-110 contributes to the sensitization of Fas-mediated apoptosis. Taken together, the alteration of the apoptosis regulatory proteins by a proteasome inhibitor induces apoptosis in tumor cells.
Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, Shizuoka 410-0301, Japan. iijimam@bikaken.or.jp
Masatomi
M
Iijima
Isao
I
Momose
Daishiro
D
Ikeda
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D061988:Proteasome Inhibitors; D014407:Tumor Cells, Cultured
C506903:1-naphthylacetyl-(O-methyl)-tyrosyl-valyl-(O-methyl)-tyrosinal; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases