Chitosan Oligosaccharides Induce Apoptosis in Human Renal Carcinoma via Reactive-Oxygen-Species-Dependent Endoplasmic Reticulum Stress
Chitosan Oligosaccharides Induce Apoptosis in Human Renal Carcinoma via Reactive-Oxygen-Species-Dependent Endoplasmic Reticulum Stress
复制标题
壳寡糖通过活性氧依赖性内质网应激诱导人肾癌细胞凋亡
DOI：
10.1021/acs.jafc.8b06941
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发表时间：
2019
影响因子：
6.1
通讯作者：
Wang Jing
中科院分区：
文献类型：
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作者：
Zhai Xingchen;Yuan Shoujun;Yang Xin;Zou Pan;Li Linna;Li Guoyou;Shao Yong;Abd El-Aty A. M.;Hacimuftuoglu Ahmet;Wang Jing
近年来，各种研究证实了天然产物作为有效的癌症预防和治疗药物的作用。本研究证实虾蟹壳低聚糖(COS)在体外和体内对人肾癌的增殖有抑制作用。首先，通过尾静脉注射合成花菁-7标记的COS(COS-Cy7)，研究了COS在体内的分布。肾脏被发现是一个主要的靶器官。在体外观察其对肾癌细胞增殖、凋亡及活性氧(ROS)产生的影响，并建立肾癌细胞原位移植瘤模型，以评价其体内抗肿瘤作用。在肾癌细胞中，COS以ROS依赖的方式诱导G2/M期阻滞和细胞凋亡。COS显著促进核因子红系2相关因子(NRF2)和NRF2靶基因，如血红素加氧酶1、谷氨酸半胱氨酸连接酶修饰亚基和溶质载体家族7成员11的表达。此外，COS还显著上调葡萄糖调节蛋白78、蛋白核糖核酸样内质网(ER)激酶、真核启动因子2α、激活转录因子4、C/EBP同源蛋白和细胞色素c的蛋白表达，从而证实了ER应激信号通路的激活。综上所述，COS在体内外抑制人肾癌生长并诱导细胞凋亡，主要是通过ROS依赖的内质网应激途径。
In recent years, various studies have confirmed the role of natural products as effective cancer prevention and treatment drugs. The present study demonstrated that chitosan oligosaccharide (COS) from shells of shrimp and crab caused an inhibitory effect on the proliferation of human renal carcinomain vitroandin vivo. First, thein vivobiodistribution of COS was investigated by the synthesis of cyanine-7-labeled COS (COS–Cy7) following tail vein injection. The kidney was found to be a major target organ. Then, the impacts on renal carcinoma cell proliferation, apoptosis, and reactive oxygen species (ROS) production were observedin vitro, and an orthotopic xenograft tumor model was designed to evaluate the antitumor efficacy of COSin vivo. In renal carcinoma cells, COS induced G2/M phase arrest and apoptosis in a ROS-dependent fashion. COS significantly promoted mRNA expression of nuclear factor erythroid 2-related factor (Nrf2) and Nrf2 target genes, such as heme oxygenase 1, modifier subunit of glutamate cysteine ligase, and solute carrier family 7 member 11. Additionally, COS significantly upregulated the protein expression of glucose-regulated protein 78, protein RNA-like endoplasmic reticulum (ER) kinase, eukaryotic initiation factor 2α, activating transcription factor 4, C/EBP homologous protein, and cytochromec, which justified the activation of the ER stress signaling pathway.In vivo, COS repressed tumor growth and induced apoptosis and ROS accumulation, consistent with thein vitroresults. Taken together, COS repressed human renal carcinoma growth and induced apoptosis bothin vitroandin vivo, mainly via ROS-dependent ER stress pathways.