Curcumin inhibits tumor proliferation induced by neutrophil elastase through the upregulation of α1‐antitrypsin in lung cancer

Abstract

A B S T R A C TLung carcinogenesis is a complex process in an unregulated inflammatory environment.Curcumin has been extensively investigated as a multi-target anti-tumor and antiinflammation 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. a1-antitrypsin is synthesized by tumor cells and is the natural inhibitor of neutrophil elastase.We found that curcumin counteracted the decrease of a1-antitrypsin induced by neutrophil elastase by inducing the promoter activity of a1-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 a1-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 a1-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 a1-antitrypsin play important roles in modulating lung tumor proliferation in inflammatory microenvironment and curcumin inhibits neutrophil elastase-induced tumor proliferation via upregulating a1-antitrypsin expression in vitro and in vivo.

Dietary agents for prevention and treatment of lung cancer

“…In tumor tissues of mice treated with curcumin, there was upregulation of α1-antitrypsin and decrease in the protein level of neutrophil elastase which play important roles in modulating lung tumor proliferation in inflammatory microenvironment. This study highlighted a new inflammation-related mechanism of curcumin against tumor proliferation and advocates the possible role of curcumin in the treatment of other inflammation-related diseases in lung such as emphysema [69]. Decrease in tumor growth and increase in survival contributed to T cell-mediated adaptive immune response was found in tumor-bearing mice treated with low-dose curcumin (50 mg/kg body weight) for ten days.…”

Curcumin and dietary polyphenol research: beyond drug discovery

“…These properties have been heavily assessed for exploring its potential utilization in cancer treatment [28,29] . In addition, a few recent studies have reported the potential effect of curcumin in promoting white adipocyte "browning" [30,31] .…”

Targeting roles of inflammatory microenvironment in lung cancer and metastasis

“…Lung cancer accounts for about 18 % (1.4 million) of the death in 2008 [8] and estimated 28 % of the death in 2012 [9]. Recent studies highlighted that chronic inflammation is critical and dependent in the complex process of lung carcinogenesis [10]. Local infections (e.g., viral infections, pneumonia, or tuberculosis) and inflammation often occur in patients with lung cancer [11].…”