Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway
Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway
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DOI：
10.1158/0008-5472.can-06-3066
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Zhang, Ruiwen
中科院分区：
文献类型：
--
作者：
Li, Mao;Zhang, Zhuo;Zhang, Ruiwen
癌蛋白MDM 2是抑癌基因p53的主要泛素E3连接酶，基于其p53依赖性和p53非依赖性活性，已被认为是人类癌症治疗的新靶点。我们已经确定了姜黄素，这已经被证明具有抗癌活性，作为MDM 2表达的抑制剂。姜黄素下调MDM 2，不依赖于p53。在人前列腺癌细胞系PC 3（p53（null））中，curcurnin以剂量和时间依赖性方式降低MDM 2蛋白和mRNA，并增强肿瘤抑制因子p21（wafl/CIP 1）的表达。抑制作用发生在转录水平，似乎涉及磷脂酰肌醇3-激酶/哺乳动物雷帕霉素靶/成红细胞增多症病毒转录因子2途径。姜黄素可诱导PC 3细胞凋亡并抑制其增殖，但MDM 2的过表达和敲低均降低了这些作用。姜黄素还抑制这些细胞的生长，并增强吉西他滨的细胞毒性作用。当将curcurnin给药于荷瘤裸鼠时，curcurnin抑制了PC 3异种移植物的生长，并增强了吉西他滨和放射的抗肿瘤作用。在这些肿瘤中，curcurnin降低了MDM 2的表达。姜黄素下调MDM 2癌基因是一种新的作用机制，可能是其化学预防和化疗作用所必需的。我们的观察有助于阐明有丝分裂原上调MDM 2的过程，独立于p53，并确定姜黄素作为抗癌剂的机制。
The oncoprotein MDM2, a major ubiquitin E3 ligase of tumor suppressor p53, has been suggested as a novel target for human cancer therapy based on its p53-dependent and p53-independent activities. We have identified curcumin, which has previously been shown to have anticancer activity, as an inhibitor of MDM2 expression. Curcumin down-regulates MDM2, independent of p53. In a human prostate cancer cell lines PC3 (p53(null)), curcurnin reduced MDM2 protein and mRNA in a dose- and time-dependent manner, and enhanced the expression of the tumor suppressor p21(wafl/CIP1). The inhibitory effects occur at the transcriptional level and seem to involve the phosphatidylinositol 3-kinase/mammalian target of rapamycin/erythroblastosis virus transcription factor 2 pathway. Curcumin induced apoptosis and inhibited proliferation of PC3 cells in culture, but both MDM2 over-expression and knockdown reduced these effects. Curcumin also inhibited the growth of these cells and enhanced the cytotoxic effects of gemcitabine. When it was administered to tumor-bearing nude mice, curcurnin inhibited growth of PC3 xenografts and enhanced the antitumor effects of gemcitabine and radiation. In these tumors, curcurnin reduced the expression of MDM2. Down-regulation of the MDM2 oncogene by curcumin is a novel mechanism of action that may be essential for its chernopreventive and chemotherapeutic effects. Our observations help to elucidate the process by which mitogens up-regulate MDM2, independent of p53, and identify a mechanism by which curcumin functions as an anticancer agent.