Wogonin induces cross-regulation between autophagy and apoptosis via a variety of Akt pathway in human nasopharyngeal carcinoma cells
Wogonin induces cross-regulation between autophagy and apoptosis via a variety of Akt pathway in human nasopharyngeal carcinoma cells
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DOI：
10.1002/jcb.24224
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发表时间：
2012-11-01
影响因子：
4
通讯作者：
Wang, Jong-Shyan
中科院分区：
文献类型：
--
作者：
Chow, Shu-Er;Chen, Yu-Wen;Wang, Jong-Shyan
自噬和细胞凋亡是癌症治疗的新兴靶点。黄芩素是一种从中药黄芩中提取的类黄酮化合物，对包括人鼻咽癌在内的多种肿瘤细胞具有抗肿瘤活性。然而，自噬在wogonin诱导的鼻咽癌细胞凋亡中的作用尚不清楚。在本研究中，我们发现wogonin诱导的自噬对细胞凋亡过程有干扰作用。通过LC3 I/II切割、吖啶橙（AO）染色的液泡和TEM分析的自噬体/自噬体图像证明了wogonin诱导的自噬形成。雷帕霉素通过抑制mTOR/P70S6K途径激活自噬，导致wogonin介导的自噬增加。通过膜联蛋白v阳性染色细胞和PARP切割研究自噬在抗肿瘤活性中的功能相关性。雷帕霉素诱导细胞自噬可改善沃戈宁介导的细胞凋亡，而3-甲基腺嘌呤（3-MA）或巴菲霉素A1抑制细胞自噬可增强细胞凋亡作用。有趣的是，本研究还发现，除了mTOR/P70S6K通路外，wogonin还抑制了多种Akt通路Raf/ERK通路。PI3K/Akt抑制剂的失活可显著诱导细胞凋亡，并使鼻咽癌细胞对wogonin诱导的细胞凋亡显着敏感。Akt的特异性抑制剂SH6进一步证实了Akt的这种抗癌作用。重要的是，MEK抑制剂PD98059使其下游分子ERK失活也能诱导细胞凋亡。本研究表明wogonin可通过多种Akt通路诱导细胞自噬和凋亡，提示调节细胞自噬可能具有深远的潜在治疗作用。j .细胞。中国生物医学工程学报，2012,31(3):376 - 385。(C) 2012 Wiley期刊公司
Autophagy as well as apoptosis is an emerging target for cancer therapy. Wogonin, a flavonoid compound derived from the traditional Chinese medicine of Huang-Qin, has anticancer activity in many cancer cells including human nasopharyngeal carcinoma (NPC). However, the involvement of autophagy in the wogonin-induced apoptosis of NPC cells was still uninvestigated. In this study, we found wogonin-induced autophagy had interference on the process of apoptosis. Wogonin-induced autophagy formation evidenced by LC3 I/II cleavage, acridine orange (AO)-stained vacuoles and the autophagosome/autolysosome images of TEM analysis. Activation of autophagy with rapamycin resulted in increased wogonin-mediated autophagy via inhibition of mTOR/P70S6K pathway. The functional relevance of autophagy in the antitumor activity was investigated by annexin V-positive stained cells and PARP cleavage. Induction of autophagy by rapamycin ameliorated the wogonin-mediated apoptosis, whereas inhibition of autophagy by 3-methyladenine (3-MA) or bafilomycin A1 increased the apoptotic effect. Interestingly, this study also found, in addition the mTOR/P70S6K pathway, wogonin also inhibited Raf/ERK pathway, a variety of Akt pathways. Inactivation of PI3K/Akt by their inhibitors significantly induced apoptosis and markedly sensitized the NPC cells to wogonin-induced apoptosis. This anticancer effect of Akt was further confirmed by SH6, a specific inhibitor of Akt. Importantly, inactivation of its downstream molecule ERK by PD98059, a MEK inhibitor, also induced apoptosis. This study indicated wogonin-induced both autophagy and apoptosis through a variety of Akt pathways and suggested modulation of autophagy might provide profoundly the potential therapeutic effect. J. Cell. Biochem. 113: 34763485, 2012. (C) 2012 Wiley Periodicals, Inc.