State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University and Institute of System Biomedicine, Peking University, Beijing 100191, China.
Mol Oncol. 2012 Aug;6(4):405-17. doi: 10.1016/j.molonc.2012.03.005. Epub 2012 Apr 2.
Lung carcinogenesis is a complex process in an unregulated inflammatory environment. Curcumin has been extensively investigated as a multi-target anti-tumor and anti-inflammation compound. In this paper, we demonstrate a novel inflammation-related mechanism for curcumin-induced inhibition of lung tumor growth. We found that neutrophil elastase, an important regulator of inflammatory processes, directly triggered tumor cell proliferation in human lung adenocarcinoma A549 cells, and curcumin could completely suppress the excess tumor proliferation induced by neutrophil elastase. α1-antitrypsin is synthesized by tumor cells and is the natural inhibitor of neutrophil elastase. We found that curcumin counteracted the decrease of α1-antitrypsin induced by neutrophil elastase by inducing the promoter activity of α1-antitrypsin and promoting its expression in A549 cells. The inhibition of neutrophil elastase-induced proliferation by curcumin was dependent on the PI3K/Akt pathway. Knockdown of α1-antitrypsin by siRNA further enhanced the tumor cell proliferation induced by neutrophil elastase and significantly blocked the anti-proliferation effect of curcumin against neutrophil elastase. Curcumin remarkably inhibited the primary tumor growth of Lewis lung carcinoma (LLC) in C57BL/6 mice. We further showed that curcumin upregulated the level of α1-antitrypsin in primary tumor tissue by promoting its local expression, and the protein level of neutrophil elastase in tumor tissue was obviously decreased in mice treated with curcumin. Overall, our results suggest that neutrophil elastase and α1-antitrypsin play important roles in modulating lung tumor proliferation in inflammatory microenvironment and curcumin inhibits neutrophil elastase-induced tumor proliferation via upregulating α1-antitrypsin expression in vitro and in vivo.
肺癌发生是一个在不受调控的炎症环境中的复杂过程。姜黄素作为一种多靶点抗肿瘤和抗炎化合物已被广泛研究。在本文中，我们证明了姜黄素抑制肺肿瘤生长的一个新的与炎症相关的机制。我们发现，中性粒细胞弹性蛋白酶，一个炎症过程的重要调节因子，直接触发人肺腺癌细胞 A549 的肿瘤细胞增殖，而姜黄素可以完全抑制中性粒细胞弹性蛋白酶诱导的肿瘤过度增殖。α1-抗胰蛋白酶是由肿瘤细胞合成的，是中性粒细胞弹性蛋白酶的天然抑制剂。我们发现姜黄素通过诱导α1-抗胰蛋白酶启动子活性和促进其在 A549 细胞中的表达，拮抗了中性粒细胞弹性蛋白酶诱导的α1-抗胰蛋白酶减少。姜黄素抑制中性粒细胞弹性酶诱导的增殖依赖于 PI3K/Akt 通路。用 siRNA 敲低α1-抗胰蛋白酶进一步增强了中性粒细胞弹性酶诱导的肿瘤细胞增殖，并显著阻断了姜黄素对中性粒细胞弹性酶的抗增殖作用。姜黄素显著抑制 C57BL/6 小鼠Lewis 肺癌（LLC）的原发肿瘤生长。我们进一步表明，姜黄素通过促进其局部表达，上调了原发性肿瘤组织中α1-抗胰蛋白酶的水平，并用姜黄素处理的小鼠肿瘤组织中中性粒细胞弹性蛋白酶的蛋白水平明显降低。总的来说，我们的结果表明，中性粒细胞弹性蛋白酶和α1-抗胰蛋白酶在调节炎症微环境中的肺肿瘤增殖中发挥重要作用，姜黄素通过在体外和体内上调α1-抗胰蛋白酶的表达来抑制中性粒细胞弹性酶诱导的肿瘤增殖。
