Anthraquinone emodin inhibits human cancer cell invasiveness by antagonizing P2X7 receptors
Anthraquinone emodin inhibits human cancer cell invasiveness by antagonizing P2X7 receptors
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DOI：
10.1093/carcin/bgt099
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发表时间：
2013-07-01
期刊：
影响因子：
4.7
通讯作者：
Roger, Sebastien
中科院分区：
文献类型：
--
作者：
Jelassi, Bilel;Anchelin, Monique;Roger, Sebastien
腺苷 5'-三磷酸 (ATP) 门控 Ca-2 通透性通道 P2X7 受体 (P2X7R) 在许多肿瘤和癌细胞中强烈上调，并且在与转移相关的癌细胞侵袭中发挥重要作用。大黄素（1,3,8-三羟基-6-甲基蒽醌）是一种蒽醌衍生物，最初从大黄中分离出来，几十年来一直被认为具有抗癌特性。在这项研究中，我们利用高度侵袭性的人类癌细胞，研究了大黄素对 P2X7R 依赖性 Ca-2 信号传导、细胞外基质降解以及体外和体内癌细胞侵袭性的影响。在细胞培养物中加入10 M剂量的大黄素对细胞活力没有影响或影响非常轻微。 1 和 10 M 大黄素分别使 ATP 引起的细胞内 Ca-2 浓度增加降低 35% 和 60%。大黄素特异性抑制 P2X7R 介导的电流，IC50 为 3 M，并且不抑制人胚胎肾 (HEK293T) 细胞中异源表达的其他人 P2X 受体介导的电流。 1 M 大黄素可防止 ATP 诱导的明胶分解活性、体外癌细胞侵袭力和细胞形态变化的增加。此外，这种 ATP 诱发的效应和大黄素的抑制作用在用 P2X7R 特异性小干扰 RNA (siRNA) 转染的癌细胞中几乎完全消除，但用乱序 siRNA 转染则不然。最后，使用斑马鱼微转移模型评估，P2X7R 阳性 MDA-MB-435s 乳腺癌细胞的体内侵袭性被 1 和 10 M 大黄素抑制了 40% 和 50%。综上所述，这些结果提供了一致的证据，表明大黄素通过特异性拮抗 P2X7R 来抑制人类癌细胞的侵袭。
The adenosine 5'-triphosphate (ATP)-gated Ca-2-permeable channel P2X7 receptor (P2X7R) is strongly upregulated in many tumors and cancer cells, and has an important role in cancer cell invasion associated with metastases. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is an anthraquinone derivative originally isolated from Rheum officinale Baill known for decades to possess anticancer properties. In this study, we examined the effects of emodin on P2X7R-dependent Ca-2 signaling, extracellular matrix degradation, and in vitro and in vivo cancer cell invasiveness using highly aggressive human cancer cells. Inclusion of emodin at doses 10 M in cell culture had no or very mild effect on the cell viability. ATP elicited increases in intracellular Ca-2 concentration were reduced by 35 and 60% by 1 and 10 M emodin, respectively. Emodin specifically inhibited P2X7R-mediated currents with an IC50 of 3 M and did not inhibit the currents mediated by the other human P2X receptors heterologously expressed in human embryonic kidney (HEK293T) cells. ATP-induced increase in gelatinolytic activity, in cancer cell invasiveness in vitro and in cell morphology changes were prevented by 1 M emodin. Furthermore, such ATP-evoked effects and inhibition by emodin were almost completely ablated in cancer cells transfected with P2X7R-specific small interfering RNA (siRNA) but not with scrambled siRNA. Finally, the in vivo invasiveness of the P2X7R-positive MDA-MB-435s breast cancer cells, assessed using a zebrafish model of micrometastases, was suppressed by 40 and 50% by 1 and 10 M emodin. Taken together, these results provide consistent evidence to indicate that emodin inhibits human cancer cell invasiveness by specifically antagonizing the P2X7R.