Lung cancer is the main cause of cancer incidence and mortality around the world. Prucalopride is an agonist for the 5-hydroxytryptamine 4 receptor, but it was unknown whether prucalopride could be used to treat lung cancer. To investigate the biological effects of prucalopride on proliferation, apoptosis, invasion, and migration of lung cancer cells, and its underlying molecular mechanism in the progression of lung cancer, we performed this study. The Cell Counting Kit 8 assay was used to measure the proliferation of A549/A427 lung cancer cells treated with prucalopride. Transwell assay was applied to evaluate cell invasion and migration. Cell apoptosis was detected by flow cytometry and Western blot analyses. The expression levels of related proteins in the PI3K/AKT/mTor signaling pathway were analyzed by Western blotting. Prucalopride inhibited the proliferation, invasion, and migration of A549/A427 human lung cancer cells. It also induced autophagy and apoptosis and decreased the expression of the phosphorylated protein kinase B (AKT) and mammalian target of rapamycin (mTor) in these cells. This study implied an inhibitory role for prucalopride in the progression of human lung cancer.
Background: E1A gene therapy was tested in multiple clinical trials in breast, ovarian, and head and neck cancers. E1A can sensitize paclitaxel-induced cell death and combined paclitaxel chemotherapy and E1A gene therapy is currently tested in a clinical trial for ovarian cancer patients. It has been shown that resistance to paclitaxel occurs in cells expressing low level of FOXO3a. We found that Forkhead box O-class (FOXO) transcription factor FOXO3a is critical for E1A-mediated chemosensitization to paclitaxel. Knocked down FOXO3a expression dramatically abolished E1A-induced chemosensitization of paclitaxel. E1A stabilized FOXO3a by preventing ubiquitin-dependent proteolysis. The E3 ligase involved in stabilizing FOXO3a is β-transducin repeat-containing proteins (ßTrCP); ßTrCP binding to FOXO3a requires phosphorylation of FOXO3a at Ser644 by IKKβ. E1A reduces βTrCP-mediated ubiquitination of FOXO3a by inhibiting IKKβ activity. Further, inhibited IKKß activity is due to E1A-induced expression of PP2A, which binds to transforming growth factor β-activated kinase 1 (TAK1), thus inhibiting TAK1's activation of IKKβ. In this study, we found that E1A stabilizes FOXO3a which is required to sensitize paclitaxel-induced apoptosis. The stabilization is achieved by E1A-induced expression of PP2A/C, which inhibits the binding of TAK1 to IKKβ, therefore abolishing IKKß's function in phosphorylating FOXO3a and FOXO3a degradation. This result provides a rationale for the combination of E1A gene therapy and paclitaxel chemotherapy and may also shed light on design of targeted therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-05-10.
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