Honokiol Eliminates Glioma/Glioblastoma Stem Cell-Like Cells via JAK-STAT3 Signaling and Inhibits Tumor Progression by Targeting Epidermal Growth Factor Receptor
Honokiol Eliminates Glioma/Glioblastoma Stem Cell-Like Cells via JAK-STAT3 Signaling and Inhibits Tumor Progression by Targeting Epidermal Growth Factor Receptor
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和厚朴酚通过 JAK-STAT3 信号消除神经胶质瘤/胶质母细胞瘤干细胞样细胞，并通过靶向表皮生长因子受体抑制肿瘤进展
DOI：
10.3390/cancers11010022
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发表时间：
2019-01-01
期刊：
影响因子：
5.2
通讯作者：
Zhao, Weijiang
中科院分区：
文献类型：
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作者：
Fan, Yipu;Xue, Weikang;Zhao, Weijiang
恶性神经胶质瘤是最具侵袭性的脑肿瘤。其转移和复发导致高发病率和死亡率。神经胶质瘤干细胞样细胞是负责神经胶质瘤肿瘤发生、转移、复发和治疗耐药的肿瘤起始细胞亚群。据报道，表皮生长因子受体（EGFR）在大多数癌症（包括神经胶质瘤）中失调，其功能与肿瘤转移的起始和非常差的预后密切相关。在寻找可能降低神经胶质瘤/胶质母细胞瘤致瘤潜力的化合物时，和厚朴酚引起了我们的注意。和厚朴酚是从传统中草药厚朴树皮中纯化出来的，在体外和动物模型中具有多种药理作用，包括抗炎、抗血管生成、抗心律失常和抗氧化活性，以及对多种人类癌细胞的抗增殖和促凋亡作用。然而，它对神经胶质瘤细胞的影响尚不清楚。在这里，我们使用不同浓度的和厚朴酚处理细胞培养物中的 U251 和 U-87 MG 人胶质瘤/胶质母细胞瘤细胞。结果表明和厚朴酚抑制神经胶质瘤细胞活力和集落形成并促进细胞凋亡。它还抑制神经胶质瘤细胞迁移/增殖和侵袭。此外，和厚朴酚促进细胞凋亡并降低Bcl-2表达，同时增加Bax表达。和厚朴酚降低 EGFR、CD133 和 Nestin 的表达。此外，和厚朴酚还能抑制 AKT 和 ERK 信号通路的激活，增加活性 caspase-3 水平并减少 STAT3 的磷酸化。裸鼠和免疫耐受斑马鱼卵黄囊中的 U-87 MG 异种移植物表明和厚朴酚可抑制肿瘤生长和转移。总而言之，结果表明和厚朴酚可降低致瘤潜力，这表明和厚朴酚有望用于神经胶质瘤/胶质母细胞瘤的临床治疗。
Malignant gliomas are the most aggressive forms of brain tumors; whose metastasis and recurrence contribute to high rates of morbidity and mortality. Glioma stem cell-like cells are a subpopulation of tumor-initiating cells responsible for glioma tumorigenesis, metastasis, recurrence and resistance to therapy. Epidermal growth factor receptor (EGFR) has been reported to be dysregulated in most cancers, including gliomas and its functions are closely linked to initiating tumor metastasis and a very poor prognosis. In search for compounds that may reduce the tumorigenic potential of gliomas/glioblastomas honokiol attracted our attention. Honokiol, purified from the bark of traditional Chinese herbal medicine Magnolia species, is beneficial in vitro and in animal models via a variety of pharmacological effects, including anti-inflammatory, anti-angiogenetic, anti-arrhythmic and antioxidant activities, as well as anti-proliferative and proapoptotic effects in a wide range of human cancer cells. However, its effects on glioma cells are unknown. Here, we used different concentrations of honokiol in treating U251 and U-87 MG human glioma/glioblastoma cells in cell culture. Results showed that honokiol inhibited glioma cell viability and colony formation and promoted apoptosis. It also inhibited glioma cell migration/proliferation and invasion. In addition, honokiol promoted apoptosis and reduced Bcl-2 expression, accompanied by increase in Bax expression. Honokiol reduced expression of EGFR, CD133 and Nestin. Moreover, honokiol inhibited the activation of both AKT and ERK signaling pathways, increased active caspase-3 level and reduced phosphorylation of STAT3. U-87 MG xenografts in nude mice and in immunotolerant zebrafish yolk sac showed that honokiol inhibits tumor growth and metastasis. Altogether, results indicate that honokiol reduces tumorigenic potentials, suggesting hopes for honokiol to be useful in the clinical management of glioma/glioblastoma.