Nobiletin inhibits human osteosarcoma cells metastasis by blocking ERK and JNK-mediated MMPs expression

// Hsin-Lin Cheng 1 , Ming-Ju Hsieh 1, 2 , Jia-Sin Yang 1, 3 , Chiao-Wen Lin 4, 5 , Ko-Haung Lue 6, 7 , Ko-Hsiu Lu 6, 8 , Shun-Fa Yang 1, 3 1 Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan 2 Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan 3 Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan 4 Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan 5 Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan 6 School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan 7 Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan 8 Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 40201, Taiwan Correspondence to: Ko-Hsiu Lu, e-mail: cshy307@csh.org.tw Shun-Fa Yang, e-mail: ysf@csmu.edu.tw Keywords: nobiletin, metastasis, MMP, CREB, SP-1 Received: December 01, 2015      Accepted: April 11, 2016      Published: April 29, 2016 ABSTRACT 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.