Curcumol Inhibits Lung Adenocarcinoma Growth and Metastasis via Inactivation of PI3K/AKT and Wnt/-Catenin Pathway

Abstract

Curcumol (Cur), isolated from the Traditional Chinese Medical plant Rhizoma Curcumae, is the bioactive component of sesquiterpene reported to possess antitumor activity. However, its bioactivity and mechanisms against lung adenocarcinoma are still unclear. We investigated its effect on lung adenocarcinoma and elucidated its underlying molecular mechanisms. In vitro, Cur effectively suppressed proliferation, migration, and invasion of lung adenocarcinoma cells A549 and H460, which were associated with the altered expressions of signaling molecules, including p-AKT, p-PI3K, p-LRP5/6, AXIN, APC, GSK3 and p--catenin, matrix metalloproteinase (MMP)-2, and MMP-9. Furthermore, Cur significantly induced cell apoptosis of A549 and H460 by promoting the expression of Bax, caspase 3, and caspase 9 and suppressing the expression of Bcl-2, and arrested the cell cycle at the G0/G1 phase by lowering the levels of cyclin D1, CDK1, and CDK4. In vivo experiment revealed that Cur could inhibit lung tumor growth and lung metastasis, which were consistent with these in vitro results. In xenograft model mice, Cur strongly decreased tumor weight and tumor volume, which may be related to the downregulation of p-AKT and p-PI3K by immunofluorescence analysis. In addition, a lung metastasis model experiment suggested that Cur dramatically decreased the ratio of lung/total weight, tumor metastatic nodules, and the expressions of MMP-2 and MMP-9 in lung tissues compared with the control. Overall, these data suggested that the inhibitory activity of Cur on lung adenocarcinoma via the inactivation of PI3K/Akt and Wnt/-catenin pathways, at least in part, indicates that curcumol may be a potential antitumor agent for lung adenocarcinoma therapy.