Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation
Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation
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DOI：
10.7150/thno.34674
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Jiang, Jian-Dong
中科院分区：
文献类型：
--
作者：
Huang, Shuai;Wang, Lu-Lu;Jiang, Jian-Dong
基本原理：诱导癌症分化是治疗癌症的一种有前途的方法。在这里，我们确定了绿原酸（CA），一个潜在的分化诱导剂，用于癌症治疗，并阐明其分化诱导作用对癌细胞的分子机制。方法：癌细胞分化进行了研究，通过测量恶性行为，包括生长速度，侵袭/迁移，形态学变化，成熟，和ATP的生产。通过微阵列分析、qRT-PCR和蛋白质测量分析基因表达，并采用分子生物学技术进行机制研究。LC/MS分析是化学检测的首选方法。结果：CA处理的癌细胞增殖率、迁移/侵袭能力和线粒体ATP生成均降低。用CA处理癌细胞通过作用于其3 'UTR并稳定mRNA而导致SUMO]表达升高。增加的SUMO]引起c-Myc类小泛素化、miR-17家族下调和p21上调，导致G（0）/G（1）停滞和成熟表型。CA改变了癌细胞中分化相关基因的表达，但在正常细胞中没有。它能抑制荷瘤小鼠肝癌和肺癌的生长，并能预防未接种小鼠的新肿瘤发生。在胶质瘤细胞中，CA增加特异性分化生物标志物Tuj 1和GFAP的表达，诱导分化并减少球体形成。CA对胶质瘤细胞的治疗效果与替莫唑胺相当。CA是可检测到的血液和大脑中，当给药在动物腹腔内。结论：CA可能是一种安全有效的肿瘤诱导分化剂。“教育”癌细胞分化，而不是杀死它们，可能是一种新的癌症治疗策略。
Rationale: Inducing cancer differentiation is a promising approach to treat cancer. Here, we identified chlorogenic acid (CA), a potential differentiation inducer, for cancer therapy, and elucidated the molecular mechanisms underlying its differentiation-inducing effects on cancer cells.Methods: Cancer cell differentiation was investigated by measuring malignant behavior, including growth rate, invasion/migration, morphological change, maturation, and ATP production. Gene expression was analyzed by microarray analysis, qRT-PCR, and protein measurement, and molecular biology techniques were employed for mechanistic studies. LC/MS analysis was the method of choice for chemical detection. Finally, the anticancer effect of CA was evaluated both in vitro and in vivo.Results: Cancer cells treated with CA showed reduced proliferation rate, migration/invasion ability, and mitochondrial ATP production. Treating cancer cells with CA resulted in elevated SUMO] expression through acting on its 3'UTR and stabilizing the mRNA. The increased SUMO] caused c-Myc sumoylation, miR-17 family downregulation, and p21 upregulation leading to G(0)/G(1) arrest and maturation phenotype. CA altered the expression of differentiation-related genes in cancer cells but not in normal cells. It inhibited hepatoma and lung cancer growth in tumor-bearing mice and prevented new tumor development in naive mice. In glioma cells, CA increased expression of specific differentiation biomarkers Tuj1 and GFAP inducing differentiation and reducing sphere formation. The therapeutic efficacy of CA in glioma cells was comparable to that of temozolomide. CA was detectable both in the blood and brain when administered intraperitoneally in animals. Most importantly, CA was safe even at very high doses.Conclusion: CA might be a safe and effective differentiation-inducer for cancer therapy. "Educating" cancer cells to differentiate, rather than killing them, could be a novel therapeutic strategy for cancer.