lignans and Nasopharyngeal-Neoplasms

Nasopharyngeal carcinoma (NPC) is highly prevalent in southern China. The remote metastasis of advanced NPC requires chemotherapeutic treatments to reduce the mortality. Our previous work revealed that saucerneol (SN) showed cytotoxicity against several nasopharyngeal carcinoma (NPC) cells. This work aims to investigate the effect of SN in NPC growth and exploring the mechanism of action.. Applying in vivo study, in vitro study and in silico study to indicate the mechanism of SN in inhibiting NPC growth.. Saucerneol (SN) toxicity was measured with MTT assay. NPC proliferation was measured with EdU and colony formation assays, cell cycle was detected with flow cytometry. NPC migration and invasion were measured with scratch assay and matrigel transwell method. Further, human NPC xenograft tumor models were established in nude mice to evaluate the therapeutic efficacy of SN in vivo. Toxicological analysis was performed on H&E staining and IHC. Quantitative real-time PCR and Western blot analyses were used to evaluate the expression levels of key molecules in PI3K/AKT/mTOR, MAPK, NF-κB, and HIF-1α signal pathways. Target predicting was conducted using computational method, and target identification was carried out by ATPase assay and TSA.. SN, a potent NPC inhibitor that was previously isolated from Saururus chinensis in our lab, is proven to inhibit the proliferation and metastasis of HONE1 cell lines and inhibit the growth of human NPC xenografts in nude mice. Moreover, we further articulate the molecular mechanism of action for SN and, reveal that SN promotes the expression of cell cycle-dependent kinase inhibitory protein p21 Waf1/Cip1 through targeting Grp94 and then inhibiting PI3K/AKT signaling pathway as well as up-regulating p53 to disrupt the progression of HONE1 cells.. SN significantly inhibits NPC cells proliferation and metastasis in vitro and in vivo via selectively inhibit Grp94 and then blocking PI3K/AKT/mTOR/HIF-1α signaling pathway. This study firstly provides a novel selective Grp94 inhibitor as a NPC candidate.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Furans; Gene Expression Regulation, Neoplastic; HSP70 Heat-Shock Proteins; Humans; Lignans; Membrane Proteins; Mice; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases

Nasopharyngeal carcinoma (NPC) is a head and neck epithelial malignancy with high prevalence and represents a significant disease burden. Eudesmin is a natural lignin that has been reported to exhibit antitumor effect on lung cancer. However, the effect of eudesmin on NPC has not been investigated. The aim of the present study was to evaluate the role of eudesmin in NPC and to explore the underlying mechanism. The NPC cell lines CNE-1 and HONE-1 were treated with eudesmin for 48 h. Cell viability was measured using MTT assay. Cell apoptosis was detected using flow cytometry. The expression levels of enhancer of zeste homolog 2 (EZH2), Akt, and p-Akt were measured using Western blot analysis. We found that eudesmin inhibited cell viability and induced cell apoptosis of NPC cell lines in a dose-dependent manner. Eudesmin suppressed the expression of EZH2 and blocked the activation of Akt signaling pathway. Inhibition of Akt signaling pathway caused significant decrease in EZH2 expression. Moreover, knockdown of EZH2 attenuated the effects of Akt overexpression on cell viability and apoptosis in NPC cells. In conclusion, eudesmin exhibited antitumor activity via downregulating EZH2 expression through the inhibition of Akt signaling pathway. Eudesmin could be developed as a new pharmacologic approach for NPC treatment.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Down-Regulation; Enhancer of Zeste Homolog 2 Protein; Furans; Humans; Lignans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction