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 recentl y been shown to induce apoptosis in certain cell lines. In the present stud y, 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 p roteasome function as determined by a peptidyl-MCA substrate (LLVY-MCA and LLE-MCA), and induced apoptosis in these cell lines irrespective of Fas sen sitivity at low concentrations (similar to 10 mu M). LC induced the activat ion of caspase 3 (CPP32/Yama) and caspase 6 proteases in an identical manne r to Fas-mediated apoptosis. Moreover, LC induced the activation of caspase 8 (FLICE) protease, which is the initiator of the Fas-mediated apoptotic c ascade. Synthesized proteasome inhibitory peptide MG-115 (ZLLnV-CHO) also i nduced apoptosis in these cell lines; These results indicated that proteaso me inhibitors overcome Fas-resistance by bypassing the proximal part of the Fas signal. Inhibition of the proteasome function may be a new strategy fo r the treatment of ATL.