Theabrownin triggers DNA damage to suppress human osteosarcoma U2OS cells by activating p53 signalling pathway.
Theabrownin triggers DNA damage to suppress human osteosarcoma U2OS cells by activating p53 signalling pathway.
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茶褐素通过激活p53信号通路触发DNA损伤抑制人骨肉瘤U2OS细胞
DOI：
10.1111/jcmm.13742
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发表时间：
2018-09
影响因子：
5.3
通讯作者：
Efferth T
中科院分区：
文献类型：
--
作者：
Jin W;Zhou L;Yan B;Yan L;Liu F;Tong P;Yu W;Dong X;Xie L;Zhang J;Xu Y;Li C;Yuan Q;Shan L;Efferth T
骨肉瘤成为年轻人癌症死亡的第二大原因。目前骨肉瘤的化疗效果不理想，需要开发有效的治疗方法。茶是一种有益于人体健康的常用饮料。作为茶的主要成分，茶褐素已被报道具有抗癌活性。为了评价其抗骨肉瘤作用，我们建立了斑马鱼异种移植模型，并采用U2 OS细胞进行体内和体外试验。动物实验结果表明，TB对肿瘤生长有明显的抑制作用，且作用强于化疗。细胞数据证实TB-通过调节Mki 67、PARP、caspase 3和H2 AX触发DNA损伤并诱导U2 OS细胞凋亡，并且Western blot分析显示p53信号通路活化。当P53被siRNA敲低时，随后的下游信号传导被阻断，表明TB对U2 OS细胞（p53 wt）的p53依赖性机制。使用p53突变的骨肉瘤细胞系（HOS、SAOS-2和MG 63），我们发现TB对U2 OS细胞的抑制作用强于对p53-mut细胞系的抑制作用，但对SAOS-2细胞（p53 null）也有明显的影响，提示p53-null细胞中p53非依赖性通路的激活。有趣的是，发现茶褐素对体内正常组织没有毒性，甚至可以增加p53-wt正常细胞的活力。综上所述，茶褐素可通过p53依赖性机制引发U2 OS细胞的DNA损伤并诱导细胞凋亡，是一种有希望的骨肉瘤治疗候选药物。
Osteosarcoma becomes the second leading cause of cancer death in the younger population. Current outcomes of chemotherapy on osteosarcoma were unsatisfactory to date, demanding development of effective therapies. Tea is a commonly used beverage beneficial to human health. As a major component of tea, theabrownin has been reported to possess anti‐cancer activity. To evaluate its anti‐osteosarcoma effect, we established a xenograft model of zebrafish and employed U2OS cells for in vivo and in vitro assays. The animal data showed that TB significantly inhibited the tumour growth with stronger effect than that of chemotherapy. The cellular data confirmed that TB‐triggered DNA damage and induced apoptosis of U2OS cells by regulation of Mki67, PARP, caspase 3 and H2AX, and Western blot assay showed an activation of p53 signalling pathway. When P53 was knocked down by siRNA, the subsequent downstream signalling was blocked, indicating a p53‐dependent mechanism of TB on U2OS cells (p53 wt). Using osteosarcoma cell lines with p53 mutations (HOS, SAOS‐2 and MG63), we found that TB exerted stronger inhibitory effect on U2OS cells than that on p53‐mut cell lines, but it also exerted obvious effect on SAOS‐2 cells (p53 null), suggesting an activation of p53‐independent pathway in the p53‐null cells. Interestingly, theabrownin was found to have no toxicity on normal tissue in vivo and could even increase the viability of p53‐wt normal cells. In sum, theabrownin could trigger DNA damage and induce apoptosis on U2OS cells via a p53‐dependent mechanism, being a promising candidate for osteosarcoma therapy.
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DOI：
10.1002/wsbm.117
发表时间：
2011-05
影响因子：
7.9
作者：
Deol, Rahul C.;MacRae, Calum A.
通讯作者：
MacRae, Calum A.
影响因子：
50.5
作者：
Bielack, S.;Carrle, D.;Casali, P. G.
通讯作者：
Casali, P. G.
DOI：
10.1111/j.1749-6632.2012.06575.x
发表时间：
2012-01-01
期刊：
HEMATOPOIETIC STEM CELLS VIII
影响因子：
--
作者：
Konantz, Martina;Balci, Tugce B.;Lengerke, Claudia
通讯作者：
Lengerke, Claudia
影响因子：
4.7
作者：
通讯作者：
--
DOI：
10.1073/pnas.95.9.4997
发表时间：
1998-04-28
影响因子：
11.1
作者：
Jürgensmeier, JM;Xie, ZH;Reed, JC
通讯作者：
Reed, JC