Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.
Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.
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DOI：
10.1371/journal.pone.0102831
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hyodo I
中科院分区：
文献类型：
--
作者：
Hirai S;Endo S;Saito R;Hirose M;Ueno T;Suzuki H;Yamato K;Abei M;Hyodo I
上调sirtuin 1（SIRT 1），一种NAD+依赖性III类组蛋白脱乙酰酶，使p53脱乙酰化并抑制其转录活性，从而导致细胞存活。据报道，SIRT 1过表达可预测某些恶性肿瘤（包括胃癌）的生存率。然而，SIRT 1抑制的抗肿瘤作用在胃癌中仍然难以捉摸。在这里，我们研究了沉默调节蛋白抑制剂，tenovin-6，在7个人胃癌细胞系（4个细胞系与野生型TP 53，两个与突变型TP 53，一个与空TP 53）的抗肿瘤机制。有趣的是，tenovin-6在所有细胞系中诱导细胞凋亡，不仅是具有野生型TP 53的细胞系，而且是突变型和无效版本的细胞系，伴随着死亡受体5（DR 5）的上调。在KatoIII细胞系（TP 53-null）中，DR 5沉默显著减弱了tenovin-6诱导的细胞凋亡，表明其抗肿瘤作用背后的关键机制是基于死亡受体信号通路的激活。虽然据报道由沉默调节蛋白抑制剂引起的内质网应激在其他癌细胞系中诱导DR 5上调，但我们在用tenovin-6处理的胃癌细胞中未发现其相关分子如ATF 6、PERK和CHOP的显著活化。Tenovin-6与多西他赛或SN-38联合对胃癌细胞产生轻微至中度的协同细胞毒性。结论：tenovin-6通过上调DR 5表达对人胃癌细胞具有较强的抗肿瘤活性。我们的研究结果将有助于未来sirtuin抑制剂的临床开发。
Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.
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影响因子：
5.7
作者：
Bruzzese, Francesca;Rocco, Monia;Budillon, Alfredo
通讯作者：
Budillon, Alfredo
DOI：
10.1007/s00432-006-0116-6
发表时间：
2006-10-01
影响因子：
3.6
作者：
Engel, Dikla;Nudelman, Abraham;Rephaeli, Ada
通讯作者：
Rephaeli, Ada
影响因子：
20.3
作者：
Guo, F;Sigua, C;Bhalla, K
通讯作者：
Bhalla, K
影响因子：
3
作者：
Na, Young-Soon;Jung, Kyung-Ah;Kim, Tae Won
通讯作者：
Kim, Tae Won
影响因子：
8
作者：
Lara, E.;Mai, A.;Fraga, M. F.
通讯作者：
Fraga, M. F.