Alpha-mangostin suppresses PC-3 human prostate carcinoma cell metastasis by inhibiting matrix metalloproteinase-2/9 and urokinase-plasminogen expression through the JNK signaling pathway.
Alpha-mangostin, a component of Garcinia mangostana Linn, is a xanthone derivative shown to have antioxidant and anticarcinogen properties. In this study, we first report the antimetastatic effect of alpha-mangostin in the human prostate carcinoma cell line PC-3. The results show that alpha-mangostin exhibited an inhibitory effect on the abilities of adhesion, migration, and invasion by cell-matrix adhesion assay, wound healing assay, and Boyden chamber assay. In the cancer cell metastasis process, matrix degrading proteinases are required. Results from zymography showed that alpha-mangostin treatment could decrease the expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-plasminogen activator (u-PA) in a concentration-dependent manner. Moreover, alpha-mangostin also exerted an inhibitory effect on phosphorylation of c-Jun N-terminal kinase 1 and 2 (JNK1/2) and inhibition of activation of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Furthermore, the treatment of inhibitors specific for JNK (SP600125) to PC-3 cells could result in a reduced expression of MMP-2, MMP-9, and u-PA. These results demonstrated that alpha-mangostin could mediate PC-3 cells metastasis by reduction of MMP-2, MMP-9, and u-PA expression through the suppression of the JNK1/2 signaling pathway and inhibition of NF-kappaB and AP-1 binding activity. These findings proved that alpha-mangostin might be offered further application as an antimetastatic agent.
Hung
Shun-Hsing
SH
Division of Urology, Department of Surgery, Chi Mei Medical Center, No. 901, Jhong-Hua Road, Yong-Kang, Tainan 710, Taiwan, Republic of China.
Shen
Kun-Hung
KH
Wu
Cheng-Hsun
CH
Liu
Chang-Liang
CL
Shih
Yuan-Wei
YW
D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*; D044004:Xanthones / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D044004:Xanthones; D048031:JNK Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; C021053:mangostin