Astragalus polysaccharide combined with 10-hydroxycamptothecin inhibits metastasis in non-small cell lung carcinoma cell lines via the MAP4K3/mTOR signaling pathway

Non-small cell lung carcinoma (NSCLC) is a life-threatening malignancy. The level of the cell growth regulator mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3) has been shown to be correlated with a high risk of NSCLC recurrence and poor recurrence-free survival rate. The present study examined the effects of Astragalus polysaccharide (APS) and 10-hydroxycamptothecin (HCPT), which are associated with marked suppression and dephosphorylation of the MAP4K3/mammalian target of rapamycin (mTOR) signaling pathway, in the H1299 NSCLC cell line. APS and HCPT decreased H1299 cell viability, induced apoptosis and altered the cell cycle stages, as evaluated using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometric analysis. Furthermore, APS increased the expression of apoptosis-associated genes B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX), of proteases cysteine-aspartic acid protease (caspase)-3 and -9, and of cytochrome c. HCPT promoted autophagy in H1299 cells, with concomitant suppression of the expression of MAP4K3 and downregulation of mTOR signaling. Notably, combination treatment with the two agents reduced the migration and invasion of H1299 cells compared with the single treatments. It was also demonstrated that the overexpression of MAP4K3 promoted the migration and invasion of H1299 cells, and that the kinase activity was essential to this. These findings suggested that MAP4K3 may be an attractive target for the treatment of NSCLC