Proteasome inhibitor PS‐341 induces growth arrest and apoptosis of non‐small cell lung cancer cells via the JNK/c‐Jun/AP‐1 signaling

Proteasome inhibitor PS‐341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of NF‐κB 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 p21waf1 and p53, and down‐regulation of bcl‐2 protein in these cells. Also, PS‐341 caused phosphorylation of c‐Jun NH2‐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 p21waf1 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 p21waf1 playing the central role. Thus, PS‐341 might be useful for the treatment of individuals with NSCLC.