Cordycepin Augments the Chemosensitivity of Human Glioma Cells to Temozolomide by Activating AMPK and Inhibiting the AKT Signaling Pathway
Cordycepin Augments the Chemosensitivity of Human Glioma Cells to Temozolomide by Activating AMPK and Inhibiting the AKT Signaling Pathway
复制标题
虫草素通过激活 AMPK 和抑制 AKT 信号通路增强人胶质瘤细胞对替莫唑胺的化疗敏感性
DOI：
10.1021/acs.molpharmaceut.8b00551
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发表时间：
2018-11-01
影响因子：
4.9
通讯作者：
Chen, Yong
中科院分区：
文献类型：
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作者：
Bi, Yiming;Li, Han;Chen, Yong
多形性胶质母细胞瘤（GBM）是成人中最常见的致命脑癌亚型。它有很高的复发率，并表现出积极的增殖。新型细胞毒性药物替莫唑胺（TMZ）现在经常被用作GBM的一线化疗治疗;然而，相当多的患者用TMZ治疗结果是难治性的。因此，迫切需要一种更有效的治疗方法来克服这一关键问题。越来越多的证据表明AMPK和AKT都被TMZ激活，而只有AMPK通过抑制哺乳动物雷帕霉素靶蛋白（mTOR）而促进细胞凋亡。因此，AKT增加了各种肿瘤细胞的致瘤性和化学抗性。此外，AKT过表达增加胶质瘤细胞对TMZ的抗性。虫草素是蛹虫草中的主要生物活性成分，具有免疫调节、抗癌、抗氧化和抗炎等多种治疗作用。迄今为止，虫草素是否能增强GBM对TMZ的敏感性仍不清楚。本研究旨在评价虫草素联合TMZ治疗GBM的疗效，并探讨其分子机制。值得注意的是，我们发现，虫草素治疗导致抑制细胞增殖，迁移和侵袭，以及细胞凋亡和细胞周期阻滞在体外胶质瘤细胞系。同样，虫草素和TMZ的联合治疗协同地导致细胞生长、迁移和肿瘤转移的抑制以及细胞凋亡和细胞周期停滞的诱导。此外，我们还证明虫草素有效地增强AMPK的激活，抑制AKT的活性，其激活仅由TMZ诱导。此外，与单独用虫草素或TMZ处理的组相比，用虫草素和TMZ处理的组中p-mTOR、p-p70 S6 K、基质金属蛋白酶（MMP）-2和MMP-9的表达水平明显降低。在体内，联合治疗也明显缩小了肿瘤体积，延长了异种移植模型的中位生存时间。总之，我们的研究结果表明，虫草素增加TMZ敏感性在人类胶质瘤细胞至少部分通过激活AMPK和抑制AKT信号通路。总体而言，虫草素和TMZ的联合治疗可能为临床实践中GBM患者的预后提供了一种新的选择。
Glioblastoma multiforme (GBM) is the most commonly encountered subtype of deadly brain cancer in human adults. It has a high recurrence rate and shows aggressive proliferation. The novel cytotoxic agent temozolomide (TMZ) is now frequently applied as the first-line chemotherapeutic treatment for GBM; however, a considerable number of patients treated with TMZ turn out to be refractory to this drug. Hence, a more effective therapeutic approach is urgently required to overcome this critical issue. Accumulating evidence has shown that both AMPK and AKT are activated by TMZ, while only AMPK contributes to apoptosis via mammalian target of rapamycin (mTOR) inhibition. Accordingly, AKT increases the tumorigenicity and chemoresistance of various tumor cells. In addition, AKT overexpression increases the resistance of glioma cells to TMZ. Cordycepin, a major bioactive component in Cordyceps militaris, exhibits immunomodulatory, anticancer, antioxidant, and anti-inflammatory activities, among other therapeutic effects. To date, whether GBM sensitivity to TMZ can be enhanced by cordycepin largely remains unknown. In the present study, we evaluated the effect of the combined use of cordycepin and TMZ in the treatment of GBM and explored the molecular mechanisms. Notably, we found that treatment with cordycepin led to inhibition of cellular proliferation, migration, and invasion as well as cellular apoptosis and cell cycle arrest in glioma cell lines in vitro. Likewise, the combined treatment with both cordycepin and TMZ synergistically resulted in inhibition of cellular growth, migration, and tumor metastasis as well as induction of cellular apoptosis and cell cycle arrest. Moreover, we also demonstrated that cordycepin effectively enhanced the activation of AMPK and suppressed the activity of AKT, whose activation was only induced by TMZ. Furthermore, there was an apparent reduction in the expression levels of p-mTOR, p-p70S6K, matrix metalloproteinase (MMP)-2, and MMP-9 in the group treated with both cordycepin and TMZ, in comparison with those in the groups treated with either cordycepin or TMZ alone. In vivo, the combination therapy also obviously reduced the tumor volume as well as prolonged the median survival time of xenograft models. In brief, our results suggested that cordycepin augments TMZ sensitivity in human glioma cells at least partially through activation of AMPK and suppression of the AKT signaling pathway. Overall, the combination therapy of cordycepin and TMZ potentially provides a novel option for a better prognosis of patients with GBM in clinical practice.