Oroxylin A induces autophagy in human malignant glioma cells via the mTOR‐STAT3‐Notch signaling pathway
Oroxylin A induces autophagy in human malignant glioma cells via the mTOR‐STAT3‐Notch signaling pathway
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DOI：
10.1002/mc.22212
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发表时间：
2015-11
影响因子：
4.6
通讯作者：
Meijuan Zou;Chen Hu;Q. You;Aixia Zhang;Xuerong Wang;Q. Guo
中科院分区：
文献类型：
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作者：
Meijuan Zou;Chen Hu;Q. You;Aixia Zhang;Xuerong Wang;Q. Guo
自噬是一种受严格调控的分解代谢途径，涉及细胞蛋白质、细胞质和细胞器的降解。最近的证据表明，自噬作为一种肿瘤抑制因子在细胞死亡中发挥着潜在的作用，它的诱导，特别是与细胞凋亡的结合，可能是有益的。目前尚不清楚是否所有的癌细胞在诱导自噬时都表现出相同的机制。虽然哺乳动物靶标雷帕霉素(MTOR)被认为是自噬的负调控因子，但信号转导和转录激活因子3(STAT3)与自噬的关系尚未被研究。Oroxylin A是从黄芩中提取的天然单黄酮类化合物，是一种很有前途的治疗多种癌症的药物。在这里，我们研究了Oroxylin A对恶性胶质瘤细胞作用的机制。我们发现，Oroxylin A通过以剂量和时间依赖的方式诱导自噬来抑制恶性胶质瘤细胞的增殖。Oroxylin A处理可抑制AKT和ERK的激活以及mTOR和STAT3下游的磷酸化水平。此外，Oroxylin A处理降低Notch-1和髓系细胞白血病-1(Mcl-1)的表达，但上调关键的自噬相关蛋白Beclin 1的表达。3-MA(自噬抑制剂)或敲除Beclin-1可部分挽救Oroxylin A诱导的自噬细胞死亡。相反，STAT3的敲除加剧了Oroxylin A诱导的自噬细胞死亡。我们的数据揭示了自噬在增强oroxylin A诱导的细胞死亡中的重要作用，并得出结论oroxylin A通过ERK/AKT-mTOR-STAT3-Notch信号级联诱导自噬而发挥抗恶性胶质瘤的作用。©2014 Wiley期刊，Inc.
Autophagy is a tightly‐regulated catabolic pathway involving degradation of cellular proteins, cytoplasm and organelles. Recent evidence suggests that autophagy plays a potential role in cell death as a tumor suppressor and that its induction especially in combination with apoptosis could be beneficial. It remains unclear if all cancer cells behave the same mechanism when autophagy is induced. Although mammalian target of rapamycin (mTOR) is well known as a negative regulator of autophagy, the relationship between signal transducer and activator of transcription 3 (STAT3) and autophagy has not yet been investigated. Oroxylin A, a natural mono‐flavonoid extracted from Scutellariae radix, is a promising therapeutic agent for treating multiple cancers. Here we investigated the mechanism underlying the effect of oroxylin A on malignant glioma cells. We showed that oroxylin A inhibited the proliferation of malignant glioma cells by inducing autophagy in a dose‐ and time‐dependent manner. Oroxylin A treatment inhibits the AKT and ERK activation and the downstream phosphorylation level of mTOR and STAT3. In addition, oroxylin A treatment decreases the expression of Notch‐1 and myeloid cell leukemia‐1 (Mcl‐1) but upregulates Beclin 1, the key autophagy‐related protein. 3‐MA (autophagy inhibitor) or knockdown of Beclin 1 partially can rescue cells from oroxylin A‐induced autophagic cell death. In contrast, knockdown of STAT3 aggravates oroxylin A‐induced autophagic cell death. Our data reveal an important role of autophagy in enhancing cell death induced by oroxylin A and conclude that oroxylin A exerts anti‐malignant glioma proficiency by inducing autophagy via the ERK/AKT‐mTOR‐STAT3‐Notch signaling cascade. © 2014 Wiley Periodicals, Inc.