Caspase inhibitors block PS-341–induced DNA-PKcs or ATM cleavage.

(A) PS-341 induces time-dependent caspase-3 and caspase-8 cleavage in MM.1S cells. (B) PS-341 does not affect the phosphorylation of Bcl-2 or the protein expression of Bcl-2 and Bcl-xL. Immunoblotting with anti–α-tubulin antibody confirms equal protein loading. (C) Caspase-8 inhibitor Z-IETD-FMK and pan-caspase inhibitor Z-VDD-FMK protect against the PS-341–induced cleavage of DNA-PKcs and ATM and the phosphorylation of p53 through the inhibition of caspase-3 cleavage. (D) PS-341 induces time-dependent MDM2 protein cleavage in MM.1S cells. (E) Caffeine inhibits PS-341–triggered phosphorylation of p53 in a time- (upper panel) and dose- (lower panel) dependent fashion in MM.1S cells.