Nobiletin inhibits human osteosarcoma cells metastasis by blocking ERK and JNK-mediated MMPs expression
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Hsin-Lin Cheng1, Ming-Ju Hsieh1,2, Jia-Sin Yang1,3, Chiao-Wen Lin4,5, Ko-Haung Lue6,7, Ko-Hsiu Lu6,8, Shun-Fa Yang1,3
1Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
2Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan
3Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
4Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan
5Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
6School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
7Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan
8Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
Ko-Hsiu Lu, e-mail: [email protected]
Shun-Fa Yang, e-mail: [email protected]
Keywords: nobiletin, metastasis, MMP, CREB, SP-1
Received: December 01, 2015 Accepted: April 11, 2016 Published: April 29, 2016
Nobiletin, a polymethoxyflavone, has a few pharmacological activities, including anti-inflammation and anti-cancer effects. However, its effect on human osteosarcoma progression remains uninvestigated. Therefore, we examined the effectiveness of nobiletin against cellular metastasis of human osteosarcoma and the underlying mechanisms. Nobiletin, up to 100 μM without cytotoxicity, significantly decreased motility, migration and invasion as well as enzymatic activities, protein levels and mRNA expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in U2OS and HOS cells. In addition to inhibition of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), the inhibitory effect of nobiletin on the DNA-binding activity of the transcription factor nuclear factor-kappa B (NF-κB), cAMP response element-binding protein (CREB), and specificity protein 1 (SP-1) in U2OS and HOS cells. Co-treatment with ERK and JNK inhibitors and nobiletin further reduced U2OS cells migration and invasion. These results indicated that nobiletin inhibits human osteosarcoma U2OS and HOS cells motility, migration and invasion by down-regulating MMP-2 and MMP-9 expressions via ERK and JNK pathways and through the inactivation of downstream NF-κB, CREB, and SP-1. Nobiletin has the potential to serve as an anti-metastatic agent for treating osteosarcoma.
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