Synephrine Hydrochloride Suppresses Esophageal Cancer Tumor Growth and Metastatic Potential through Inhibition of Galectin-3-AKT/ERK Signaling
Synephrine Hydrochloride Suppresses Esophageal Cancer Tumor Growth and Metastatic Potential through Inhibition of Galectin-3-AKT/ERK Signaling
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盐酸辛弗林通过抑制 Galectin-3-AKT/ERK 信号传导抑制食管癌肿瘤生长和转移潜力
DOI：
10.1021/acs.jafc.8b04020
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发表时间：
2018
影响因子：
6.1
通讯作者：
Li Bin
中科院分区：
文献类型：
--
作者：
Xu Wen Wen;Zheng Can Can;Huang Yun Na;Chen Wen You;Yang Qing Sheng;Ren Jia Yi;Wang Yue Ming;He Qing Yu;Liao Hua Xin;Li Bin
使用由 429 种食物源化合物组成的库来筛选具有食管鳞状细胞癌 (ESCC) 抗癌特性的天然产物。我们首次证明，辛弗林（一种从柑橘树叶子中分离出来的活性化合物）可显着抑制细胞增殖（第 5 天，20 μM 辛弗林的抑制率：KYSE30 和 KYSE270 的抑制率分别为 71.1 ± 5.8% 和 75.7 ± 6.2%）和集落形成（10 μM 辛弗林的抑制率：86.5 ± KYSE30 和 KYSE270 分别为 5.9% 和 82.3 ± 4.5%），以及迁移能力（10 μM 辛弗林抑制率：KYSE30 和 KYSE270 分别为 76.9 ± 4.4% 和 62.2 ± 5.8%）和侵袭能力（10 μM 辛弗林抑制率：73.3 ±对ESCC细胞的KYSE30和KYSE270分别为7.5%和75.3±3.4%，呈剂量依赖性，对正常食管上皮细胞没有明显的毒性作用。从机制上讲，进行定量蛋白质组学和生物信息学分析来探索辛弗林调节的蛋白质。 Western blot 和 qRT-PCR 数据表明，辛弗林可能下调 Galectin-3，从而使 AKT 和 ERK 通路失活。此外，我们发现辛弗林可以增强食管鳞癌对氟尿嘧啶（5-FU）的敏感性。此外，体内实验表明，辛弗林对裸鼠食管鳞癌异种移植瘤具有显着的抗肿瘤作用（20 mg/kg辛弗林的抑制率为61.3±20.5%），且未观察到对动物的副作用。总而言之，辛弗林（一种食物源天然产物）可能是食管鳞癌的潜在治疗策略。
A library consisting of 429 food-source compounds was used to screen the natural products with anticancer properties in esophageal squamous cell carcinoma (ESCC). We demonstrated for the first time that synephrine, an active compound isolated from leaves of citrus trees, markedly suppressed cell proliferation (inhibition rate with 20 μM synephrine at day 5:71.1 ± 5.8% and 75.7 ± 6.2% for KYSE30 and KYSE270, respectively) and colony formation (inhibition rate with 10 μM synephrine: 86.5 ± 5.9% and 82.3 ± 4.5% for KYSE30 and KYSE270, respectively), as well as migration (inhibition rate with 10 μM synephrine: 76.9 ± 4.4% and 62.2 ± 5.8% for KYSE30 and KYSE270, respectively) and invasion abilities (inhibition rate with 10 μM synephrine: 73.3 ± 7.5% and 75.3 ± 3.4% for KYSE30 and KYSE270, respectively) of ESCC cells in a dose-dependent manner, without significant toxic effect on normal esophageal epithelial cells. Mechanistically, quantitative proteomics and bioinformatics analyses were performed to explore the synephrine-regulated proteins. Western blot and qRT-PCR data indicated that synephrine may downregulate Galectin-3 to inactivate AKT and ERK pathways. In addition, we found that the sensitivity of ESCC to fluorouracil (5-FU) could be enhanced by synephrine. Furthermore, in vivo experiments showed that synephrine had significant antitumor effect on ESCC tumor xenografts in nude mice (inhibition rate with 20 mg/kg synephrine is 61.3 ± 20.5%) without observed side effects on the animals. Taken together, synephrine, a food-source natural product, may be a potential therapeutic strategy in ESCC.