Plumbagin suppresses epithelial to mesenchymal transition and stemness via inhibiting Nrf2-mediated signaling pathway in human tongue squamous cell carcinoma cells.
Plumbagin suppresses epithelial to mesenchymal transition and stemness via inhibiting Nrf2-mediated signaling pathway in human tongue squamous cell carcinoma cells.
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白花丹素通过抑制人舌鳞状细胞癌细胞中 Nrf2 介导的信号通路来抑制上皮间质转化和干性
DOI：
10.2147/dddt.s89621
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Qiu JX
中科院分区：
文献类型：
--
作者：
Pan ST;Qin Y;Zhou ZW;He ZX;Zhang X;Yang T;Yang YX;Wang D;Zhou SF;Qiu JX
舌鳞状细胞癌是口腔颌面部最常见的恶性肿瘤，具有高度转移的特点。白花丹素（5-hydroxy-2-methyl-1，4-naphthoquinone，PLB）是从白花丹科植物根中提取的一种天然萘醌类化合物，具有多种生物活性，包括抗癌作用。然而，PLB治疗TSCC的潜在分子靶点和潜在机制仍不清楚。本研究采用基于细胞培养中氨基酸稳定同位素标记（SILAC）的定量蛋白质组学方法，研究PLB在人舌癌细胞系SCC 25中的分子相互作用，并探讨其分子机制。蛋白质组学研究表明，PLB抑制SCC 25细胞增殖，激活死亡受体介导的凋亡途径，重塑上皮粘附连接途径，操纵核因子红细胞2相关因子2（Nrf 2）介导的氧化应激反应信号通路，并涉及许多关键功能蛋白。此外，我们验证了这些蛋白质的目标，使用Western印迹分析。验证结果表明，PLB可明显诱导SCC 25细胞周期阻滞于G2/M期，并诱导细胞发生外源性凋亡，抑制细胞的上皮间质转化（EMT）和干细胞化。值得注意的是，N-乙酰基-L-半胱氨酸（NAC）和L-谷胱甘肽（GSH）消除了PLB对SCC 25细胞的细胞周期阻滞、凋亡诱导、EMT抑制和干性减弱的影响。重要的是，PLB抑制Nrf 2从胞质溶胶到细胞核的易位，导致下游靶点表达的抑制。综上所述，这些结果表明PLB可能通过抑制SCC 25细胞中Nrf 2介导的氧化应激信号通路而作为有前途的抗癌化合物。本研究为进一步明确PLB治疗TSCC的分子靶点和机制提供了线索。
Tongue squamous cell carcinoma (TSCC) is the most common malignancy in oral and maxillofacial tumors with highly metastatic characteristics. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone; PLB), a natural naphthoquinone derived from the roots of Plumbaginaceae plants, exhibits various bioactivities, including anticancer effects. However, the potential molecular targets and underlying mechanisms of PLB in the treatment of TSCC remain elusive. This study employed stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic approach to investigate the molecular interactome of PLB in human TSCC cell line SCC25 and elucidate the molecular mechanisms. The proteomic data indicated that PLB inhibited cell proliferation, activated death receptor-mediated apoptotic pathway, remodeled epithelial adherens junctions pathway, and manipulated nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress response signaling pathway in SCC25 cells with the involvement of a number of key functional proteins. Furthermore, we verified these protein targets using Western blotting assay. The verification results showed that PLB markedly induced cell cycle arrest at G2/M phase and extrinsic apoptosis, and inhibited epithelial to mesenchymal transition (EMT) and stemness in SCC25 cells. Of note, N-acetyl-l-cysteine (NAC) and l-glutathione (GSH) abolished the effects of PLB on cell cycle arrest, apoptosis induction, EMT inhibition, and stemness attenuation in SCC25 cells. Importantly, PLB suppressed the translocation of Nrf2 from cytosol to nucleus, resulting in an inhibition in the expression of downstream targets. Taken together, these results suggest that PLB may act as a promising anticancer compound via inhibiting Nrf2-mediated oxidative stress signaling pathway in SCC25 cells. This study provides a clue to fully identify the molecular targets and decipher the underlying mechanisms of PLB in the treatment of TSCC.