title: 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.
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.
authors: School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C.
authors: Mann-Jen
authors: MJ
authors: Hour
authors: Shih-Chang
authors: SC
authors: Tsai
authors: Hsi-Chin
authors: HC
authors: Wu
authors: Meng-Wei
authors: MW
authors: Lin
authors: Jing-Gung
authors: JG
authors: Chung
authors: Jin-Bin
authors: JB
authors: Wu
authors: Jo-Hua
authors: JH
authors: Chiang
authors: Minoru
authors: M
authors: Tsuzuki
authors: Jai-Sing
authors: JS
authors: Yang
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005994:Glycerophosphates / Q000008:administration & dosage*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D052999:Quinazolinones / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D005994:Glycerophosphates; D016328:NF-kappa B; D052999:Quinazolinones; D018808:Transcription Factor AP-1; C078587:1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol; D051058:Oncogene Protein v-akt; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9