Antitumor effects of the novel quinazolinone MJ-33: Inhibition of metastasis through the MAPK, AKT, NF-κB and AP-1 signaling pathways in DU145 human prostate cancer cells

Hour,Mann-Jen; Tsai,Shih-Chang; Wu,Hsi-Chin; Lin,Meng-Wei; Chung,Jing‑Gung; Wu,Jin-Bin; Chiang,Jo-Hua; Tsuzuki,Minoru; Yang,Jai-Sing

doi:10.3892/ijo.2012.1560

Antitumor effects of the novel quinazolinone MJ-33: Inhibition of metastasis through the MAPK, AKT, NF-κB and AP-1 signaling pathways in DU145 human prostate cancer cells

Authors:
- Mann-Jen Hour
- Shih-Chang Tsai
- Hsi-Chin Wu
- Meng-Wei Lin
- Jing‑Gung Chung
- Jin-Bin Wu
- Jo-Hua Chiang
- Minoru Tsuzuki
- Jai-Sing Yang
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Affiliations: School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C., Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, R.O.C., Department of Urology, China Medical University Hospital, Taichung 404, Taiwan, R.O.C., Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan, R.O.C., Department of Biochemistry, Nihon Pharmaceutical University, Saitama 362-0806, Japan, Department of Pharmacology, China Medical University, Taichung 40402, Taiwan, R.O.C.
Published online on: July 18, 2012 https://doi.org/10.3892/ijo.2012.1560
Pages: 1513-1519

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Abstract

Quinazolinone compounds have been shown to have antitumor activity in many human cancer cell lines. In the present study, we investigated the anti-metastatic activity of MJ-33 (2-(3-ethoxyphenyl)-6-pyrrolidinylquinazolinone), a novel quinazolinone derivate, and the signaling pathway of MJ-33 in human prostate cells. MJ-33 exhibited a growth inhibitory effect on DU145, LNCaP and PC-3 cells by MTT assay. DU145 cells showed greater sensitivity to the growth inhibition of MJ-33 than that of LNCaP and PC-3 cells. MJ-33 also had an inhibitory effect on the invasion, migration and adhesion of DU145 cells using Boyden chamber transwell assays, wound-healing and adhesion assay. In addition, MJ-33 inhibited cell metastasis through the reduction of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (u-PA) enzyme activities and protein levels by gelatin zymography assay and western blot analysis, respectively. MJ-33 reduced the protein levels of p-JNK, p-p38, p-ERK, p-AKT and nuclear NF-κB (p65), c-fos and c-Jun protein levels by western blotting. Using electrophoretic mobility-shift assay (EMSA), we demonstrated that MJ-33 blocked the activation of transcription factor AP-1 (activator protein-1) and NF-κB, which led to the inhibition of MMP-2 and MMP-9 expression. Collectively, our data showed that MJ-33 decreased protein levels of MAPKs (mitogen-activated protein kinases), AKT, AP-1 and NF-κB, resulting in the inhibition of matrix metalloproteinases. Downregulation of MMP-2 and MMP-9 reduces the invasion, migration and adhesion activities of DU145 cells. MJ-33 may be a promising agent against prostate cancer metastasis.

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