Tang Su-Ni, Singh Chandan, Nall Dara, Meeker Daniel, Shankar Sharmila, Srivastava Rakesh K
Department of Pharmacology, Toxicology and Therapeutics, and Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
J Mol Signal. 2010 Aug 18;5:14. doi: 10.1186/1750-2187-5-14.
Much attention has been recently focused on the role of cancer stem cells (CSCs) in the initiation and progression of solid malignancies. Since CSCs are able to proliferate and self-renew extensively due to their ability to express anti-apoptotic and drug resistant proteins, thus sustaining tumor growth. Therefore, the strategy to eradicate CSCs might have significant clinical implications. The objectives of this study were to examine the molecular mechanisms by which epigallocathechin gallate (EGCG) inhibits stem cell characteristics of prostate CSCs, and synergizes with quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables.
Our data indicate that human prostate cancer cell lines contain a small population of CD44+CD133+ cancer stem cells and their self-renewal capacity is inhibited by EGCG. Furthermore, EGCG inhibits the self-renewal capacity of CD44+alpha2beta1+CD133+ CSCs isolated from human primary prostate tumors, as measured by spheroid formation in suspension. EGCG induces apoptosis by activating capase-3/7 and inhibiting the expression of Bcl-2, survivin and XIAP in CSCs. Furthermore, EGCG inhibits epithelial-mesenchymal transition by inhibiting the expression of vimentin, slug, snail and nuclear beta-catenin, and the activity of LEF-1/TCF responsive reporter, and also retards CSC's migration and invasion, suggesting the blockade of signaling involved in early metastasis. Interestingly, quercetin synergizes with EGCG in inhibiting the self-renewal properties of prostate CSCs, inducing apoptosis, and blocking CSC's migration and invasion. These data suggest that EGCG either alone or in combination with quercetin can eliminate cancer stem cell-characteristics.
Since carcinogenesis is a complex process, combination of bioactive dietary agents with complementary activities will be beneficial for prostate cancer prevention and/ortreatment.
最近，癌症干细胞（CSCs）在实体恶性肿瘤的发生和发展中的作用受到了广泛关注。由于CSCs能够表达抗凋亡和耐药蛋白，从而具有广泛增殖和自我更新的能力，维持肿瘤生长。因此，根除CSCs的策略可能具有重要的临床意义。本研究的目的是探讨表没食子儿茶素没食子酸酯（EGCG）抑制前列腺CSCs干细胞特性的分子机制，以及与槲皮素协同作用的机制，槲皮素是许多水果和蔬菜中常见的主要多酚和类黄酮。
我们的数据表明，人前列腺癌细胞系中含有一小部分CD44+CD133+癌症干细胞，其自我更新能力受到EGCG的抑制。此外，通过悬浮培养中的球体形成来测量，EGCG抑制了从人原发性前列腺肿瘤中分离出的CD44+α2β1+CD133+CSCs的自我更新能力。EGCG通过激活caspase-3/7并抑制CSCs中Bcl-2、survivin和XIAP的表达来诱导细胞凋亡。此外，EGCG通过抑制波形蛋白、蛞蝓蛋白、蜗牛蛋白和核β-连环蛋白的表达以及LEF-1/TCF反应性报告基因的活性来抑制上皮-间质转化，并且还阻碍CSCs迁移和侵袭，这表明早期转移相关信号传导被阻断。有趣的是，槲皮素与EGCG协同抑制前列腺CSCs的自我更新特性，诱导细胞凋亡，并阻断CSCs迁移和侵袭。这些数据表明EGCG单独或与槲皮素联合使用可以消除癌症干细胞特性。
由于致癌作用是一个复杂的过程，具有互补活性的生物活性膳食剂联合使用将有利于前列腺癌的预防和/或治疗。
