Nasopharyngeal carcinoma (NPC), a disease common in the South-East Asian population, has high lymph node metastatic ability. Melatonin, an endogenously produced substance present in animals, plants, fungi, and bacteria, has oncostatic activity via several mechanisms. The molecular mechanisms involved in melatonin-mediated tumor inhibitory potential are not completely defined. Here, we show that melatonin treatment inhibits TPA-induced cell motility by regulating the matrix metalloproteinase-9 (MMP-9) expression in NPC. We also identified the signaling cascade through which melatonin inhibits MMP-9 expression; this involves melatonin regulating the binding activity of the transcription factor specificity protein-1 (SP-1)-DNA. Our mechanistic analysis further reveals that the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway is involved in the melatonin-mediated tumor suppressor activity. Furthermore, the findings indicate a functional link between melatonin-mediated MMP-9 regulation and tumor suppressing ability and provide new insights into the role of melatonin-induced molecular and epigenetic regulation of tumor growth. Thus, we conclude that melatonin suppresses the motility of NPC by regulating TPA-induced MMP-9 gene expression via inhibiting SP-1-DNA binding ability. The results provide a functional link between melatonin-mediated SP-1 regulation and the antimetastatic actions of melatonin on nasopharyngeal carcinoma.
BackgroundNasopharyngeal carcinoma (NPC) is known for its high incidence of neck lymph node metastasis, which represents poor prognosis. The present study aimed to examine the anti-metastatic properties of Selaginella tamariscina extract (STE) in human nasopharyngeal carcinoma HONE-1 cells in vitro.MethodsCell viability was examined by MTT assay, whereas cell motility was measured by invasive, migration and would healing assays. Real-time PCR, and promoter assays confirmed the inhibitory effects of STE on matrix metalloproteinase-9 (MMP-9) mRNA level in HONE-1 cells.ResultsThe STE inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced HONE-1 cell migration and invasion in a concentration-dependent manner. By zymographic and Western blot analyses, STE was shown to inhibit the activities and expression of MMP-9. Treatment of STE on TPA-induced HONE-1 cells inhibited MMP-9 expression and ERK1/2 phosphorylation without affecting JNK and p38 phosphorylation.ConclusionsSTE inhibits MMP-9 expression and HONE-1 cell metastasis. Its inhibitory effects may involve the Src/FAK/ERK 1/2 pathway. STE may have the potential of being an anti-metastatic agent against NPC.
Licochalcone A is widely studied in different fields and possesses antiasthmatic, antibacterial, anti‐inflammatory, antioxidative, and anticancer properties. Its antimalignancy activity on renal, liver, lung, and oral cancer has been explored. However, limited studies have been conducted on the inhibitory effects of licochalcone A in human nasopharyngeal carcinoma cells. We determined cell viability using MTT assay. Cell cycle distribution and apoptotic cell death were measured via flow cytometry. Caspase activation and mitogen‐activated protein kinase‐related proteins in nasopharyngeal cancer cells in response to licochalcone A were identified by Western blot analysis. Results indicated that licochalcone A reduces cell viability and induces apoptosis, as evidenced by the upregulation of caspase‐8 and caspase‐9, caspase‐3 activation, and cleaved‐poly ADP‐ribose polymerase expression. Treatment with licochalcone A significantly increases ERK1/2, p38, and JNK1/2 activation. Co‐administration of a JNK inhibitor (JNK‐IN‐8) or p38 inhibitor (SB203580) abolishes the activation of caspase‐9, caspase‐8, and caspase‐3 protein expression during licochalcone A treatment. These findings indicate that licochalcone A exerts a cytostatic effect through apoptosis by targeting the JNK/p38 pathway in human nasopharyngeal carcinoma cells. Therefore, licochalcone A is a promising therapeutic agent for the treatment of human nasopharyngeal cancer cells.
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