Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple 
myeloma (MM) cells via inactivation of NF-kappaB in vitro and has afforded some 
objective responses in individuals with relapsed, refractory MM. However, the 
activity of PS-341 against non-hematological malignancies remains to be fully 
elucidated. In this study, we found that PS-341 induced growth arrest and 
apoptosis of NCI-H520 and -H460 non-small cell lung cancer (NSCLC) cells in 
conjunction with markedly up-regulated levels of p21(waf1) and p53, and 
down-regulation of bcl-2 protein in these cells. Also, PS-341 caused 
phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and c-Jun, and enhanced 
AP-1/DNA binding activities in these cells as measured by western blotting and 
enzyme-linked immunosorbent assay (ELISA), respectively. Interestingly, when the 
JNK/c-Jun/AP-1 signal pathway was disrupted by the JNK inhibitor SP600125, the 
ability of PS-341 to inhibit the growth of NSCLC cells and to up-regulate the 
levels of p21(waf1) in these cells was blunted, but the expression of p53 was 
sustained at a high level, suggesting that the JNK/c-Jun/AP-1 signal pathway 
might mediate the anti-lung cancer effects of PS-341, with p21(waf1) playing the 
central role. Thus, PS-341 might be useful for the treatment of individuals with 
NSCLC.