Lactacystin activates FLICE (caspase 8) protease and induces apoptosis in Fas-resistant adult T-cell leukemia cell lines.
Lactacystin (LC) is a specific inhibitor of the proteasome, and has recently been shown to induce apoptosis in certain cell lines. In the present study, we established Fas-resistant adult T-cell leukemia (ATL) cell subclones RSO4 and RST1 from their parental Fas-sensitive cell lines SO4 and ST1, and examined whether LC can overcome Fas resistance. LC completely inhibited proteasome function as determined by a peptidyl-MCA substrate (LLVY-MCA and LLE-MCA), and induced apoptosis in these cell lines irrespective of Fas sensitivity at low concentrations (approximately 10 microM). LC induced the activation of caspase 3 (CPP32/Yama) and caspase 6 proteases in an identical manner to Fas-mediated apoptosis. Moreover, LC induced the activation of caspase 8 (FLICE) protease, which is the initiator of the Fas-mediated apoptotic cascade. Synthesized proteasome inhibitory peptide MG-115 (ZLLnV-CHO) also induced apoptosis in these cell lines. These results indicated that proteasome inhibitors overcome Fas-resistance by bypassing the proximal part of the Fas signal. Inhibition of the proteasome function may be a new strategy for the treatment of ATL.
Yamada
Y
Y
Department of Laboratory Medicine, Nagasaki University School of Medicine, Japan.
Sugahara
K
K
Tsuruda
K
K
Nohda
K
K
Mori
N
N
Hata
T
T
Maeda
T
T
Hayashibara
T
T
Joh
T
T
Honda
M
M
Tawara
M
M
Tomonaga
M
M
Miyazaki
Y
Y
Kamihira
S
S
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000954:Antigens, Surface / Q000096:biosynthesis; D017209:Apoptosis; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004351:Drug Resistance / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007769:Lactams; D015458:Leukemia, T-Cell / Q000473:pathology*; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000954:Antigens, Surface; D015853:Cysteine Proteinase Inhibitors; D007769:Lactams; D019014:fas Receptor; C067713:lactacystin; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D000111:Acetylcysteine