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

Area of Science:

• Pharmacology
• Oncology
• Biochemistry

Background:

• Nobiletin, a polymethoxyflavone, exhibits anti-inflammatory and anti-cancer properties.
• The anti-metastatic effects of nobiletin on human osteosarcoma have not been previously investigated.

Purpose of the Study:

• To investigate the efficacy of nobiletin in inhibiting human osteosarcoma cell metastasis.
• To elucidate the underlying molecular mechanisms of nobiletin's anti-metastatic action.

Main Methods:

• Human osteosarcoma cell lines (U2OS and HOS) were treated with varying concentrations of nobiletin.
• Cellular motility, migration, and invasion assays were performed.
• Enzymatic activities, protein levels, and mRNA expressions of matrix metalloproteinases (MMP-2 and MMP-9) were analyzed.
• The involvement of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), nuclear factor-kappa B (NF-κB), cAMP response element-binding protein (CREB), and specificity protein 1 (SP-1) pathways was assessed.

Main Results:

• Nobiletin significantly reduced osteosarcoma cell motility, migration, and invasion without inducing cytotoxicity.
• Nobiletin suppressed the enzymatic activities, protein levels, and mRNA expressions of MMP-2 and MMP-9.
• Nobiletin inhibited the activation of ERK, JNK, NF-κB, CREB, and SP-1.
• Combined treatment with nobiletin and ERK/JNK inhibitors further enhanced the inhibition of cell migration and invasion.

Conclusions:

• Nobiletin effectively inhibits human osteosarcoma cell motility, migration, and invasion.
• The anti-metastatic effect is mediated by the downregulation of MMP-2 and MMP-9 via the ERK and JNK pathways.
• Nobiletin also inactivates downstream transcription factors NF-κB, CREB, and SP-1.
• Nobiletin demonstrates potential as an anti-metastatic therapeutic agent for osteosarcoma treatment.