Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: Role of Akt and extracellular signal-regulated kinase signaling pathways
Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: Role of Akt and extracellular signal-regulated kinase signaling pathways
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DOI：
10.1124/mol.106.033167
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发表时间：
2007-07-01
影响因子：
3.6
通讯作者：
Kondo, Yasuko
中科院分区：
文献类型：
--
作者：
Aoki, Hiroshi;Takada, Yasunari;Kondo, Yasuko
自噬是癌细胞对各种抗癌疗法的反应。它被命名为程序性细胞死亡II型，其特征是在细胞质中形成自噬空泡。Akt/哺乳动物雷帕霉素靶蛋白（mTOR）/p70核糖体蛋白S6激酶（p70 S6 K）和细胞外信号调节激酶1/2（ERK 1/2）途径是调节营养饥饿诱导的自噬的两条主要途径。这些途径也经常与多种癌细胞类型（包括恶性神经胶质瘤）的肿瘤发生相关。然而，很少有研究在抗癌治疗诱导的癌细胞自噬的背景下检查这两种信号通路，并且自噬对细胞死亡的影响仍然不清楚。在这里，我们研究了姜黄素，一种在正常细胞中具有低毒性的天然化合物，在U87-MG和U373-MG恶性胶质瘤细胞中的抗癌功效和机制。在两种细胞类型中，姜黄素诱导G（2）/M期阻滞和非凋亡性自噬细胞死亡。它抑制Akt/mTOR/p70 S6 K通路并激活ERK 1/2通路，导致诱导自噬。有趣的是，Akt通路的激活抑制姜黄素诱导的自噬和细胞毒性，而ERK 1/2通路的抑制抑制姜黄素诱导的自噬和诱导的细胞凋亡，从而导致增强的细胞毒性。这些结果表明，自噬对细胞死亡的影响可能是途径特异性的。在U87-MG皮下移植瘤模型中，姜黄素显著抑制肿瘤生长（P < 0.05），并诱导自噬。这些结果表明，姜黄素在体外和体内通过诱导自噬具有较高的抗癌功效，并值得进一步研究，以可能在恶性胶质瘤患者中的临床应用。
Autophagy is a response of cancer cells to various anticancer therapies. It is designated as programmed cell death type II and characterized by the formation of autophagic vacuoles in the cytoplasm. The Akt/mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) and the extracellular signal-regulated kinases 1/2 (ERK1/2) pathways are two major pathways that regulate autophagy induced by nutrient starvation. These pathways are also frequently associated with oncogenesis in a variety of cancer cell types, including malignant gliomas. However, few studies have examined both of these signal pathways in the context of anticancer therapy-induced autophagy in cancer cells, and the effect of autophagy on cell death remains unclear. Here, we examined the anticancer efficacy and mechanisms of curcumin, a natural compound with low toxicity in normal cells, in U87-MG and U373-MG malignant glioma cells. Curcumin induced G(2)/M arrest and nonapoptotic autophagic cell death in both cell types. It inhibited the Akt/mTOR/p70S6K pathway and activated the ERK1/2 pathway, resulting in induction of autophagy. It is interesting that activation of the Akt pathway inhibited curcumin-induced autophagy and cytotoxicity, whereas inhibition of the ERK1/2 pathway inhibited curcumin-induced autophagy and induced apoptosis, thus resulting in enhanced cytotoxicity. These results imply that the effect of autophagy on cell death may be pathway-specific. In the subcutaneous xenograft model of U87-MG cells, curcumin inhibited tumor growth significantly ( P < 0.05) and induced autophagy. These results suggest that curcumin has high anticancer efficacy in vitro and in vivo by inducing autophagy and warrant further investigation toward possible clinical application in patients with malignant glioma.