Yang Yang, Ikezoe Takeyuki, Saito Tsuyako, Kobayashi Makoto, Koeffler H Phillip, Taguchi Hirokuni
Department of Internal Medicine, Kochi Medical School, Kochi 783-8505, Japan.
Cancer Sci. 2004 Feb;95(2):176-80. doi: 10.1111/j.1349-7006.2004.tb03200.x.
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.
蛋白酶体抑制剂PS - 341在体外通过使核因子-κB失活诱导多发性骨髓瘤（MM）细胞生长停滞和凋亡，并且已使一些复发、难治性MM患者出现了客观反应。然而，PS - 341对非血液系统恶性肿瘤的活性仍有待充分阐明。在本研究中，我们发现PS - 341诱导NCI - H520和 - H460非小细胞肺癌（NSCLC）细胞生长停滞和凋亡，同时这些细胞中p21（waf1）和p53水平显著上调，bcl - 2蛋白下调。此外，PS - 341导致c - Jun氨基末端激酶（JNK）和c - Jun磷酸化，并且分别通过蛋白质印迹法和酶联免疫吸附测定（ELISA）检测发现这些细胞中AP - 1/DNA结合活性增强。有趣的是，当JNK抑制剂SP600125阻断JNK/c - Jun/AP - 1信号通路时，PS - 341抑制NSCLC细胞生长以及上调这些细胞中p21（waf1）水平的能力减弱，但p53的表达维持在高水平，这表明JNK/c - Jun/AP - 1信号通路可能介导PS - 341的抗肺癌作用，其中p21（waf1）起核心作用。因此，PS - 341可能对NSCLC患者的治疗有用。
