A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation.
A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation.
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DOI：
10.3390/ijms19092743
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发表时间：
2018-09-13
影响因子：
5.6
通讯作者：
Kim HS
中科院分区：
文献类型：
--
作者：
De U;Son JY;Sachan R;Park YJ;Kang D;Yoon K;Lee BM;Kim IS;Moon HR;Kim HS
我们之前发现了一种新型去乙酰化酶 (SIRT) 抑制剂 MHY2256，它通过 MCF-7 人乳腺癌细胞中的 p53 乙酰化发挥抗癌活性。我们研究了 MHY2256 对激素相关癌症（一种预后不良的子宫内膜癌）的抗癌活性。 MHY2256 的 IC50 值远低于众所周知的 SIRT 抑制剂 salarmide。此外，MHY2256 显着降低 SIRT1、2 和 3 的蛋白表达和活性，与 salarmide 具有相似的效果。特别是，MHY2256 显着抑制石川癌细胞肿瘤异种移植小鼠模型中的肿瘤生长。实验期间，MHY2256处理的小鼠体重没有明显变化。对石川细胞致敏机制的详细分析表明，MHY2256 大大增加了晚期细胞凋亡。此外，MHY2256 增加了 G1 期停滞并减少了细胞周期相关蛋白的数量，表明 MHY2256 的细胞凋亡是通过细胞停滞实现的。特别是，MHY225656大大增加了p21，表明p21引起的细胞周期停滞是Ishikawa细胞中MHY2256致敏的主要因素。我们还在 MHY2256 处理后的 Ishikawa 细胞中检测到乙酰化 p53（SIRT1 的靶蛋白）显着增加。在小鼠异种移植模型中，MHY2256 显着减少肿瘤生长和重量，且没有明显的副作用。这些结果表明，MHY2256 通过 p53 乙酰化在子宫内膜癌中发挥抗癌活性，可用于靶向激素相关癌症。
We previously discovered a novel sirtuin (SIRT) inhibitor, MHY2256, that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. We investigated the anticancer activity of MHY2256 against hormone-related cancer, an endometrial cancer with a poor prognosis. The IC50 values of MHY2256 were shown to be much lower than those of salermide, a well-known SIRT inhibitor. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3, with similar effects to salermide. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. A detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced the number of cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.
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影响因子：
4.8
作者：
Hoffmann, Gesine;Breitenbuecher, Frank;Ehrenhofer-Murray, Ann E.
通讯作者：
Ehrenhofer-Murray, Ann E.
影响因子：
--
作者：
Tran AQ;Gehrig P
通讯作者：
Gehrig P
影响因子：
4.7
作者：
Ahn, Mee Young;Jung, Jee H.;Kim, Hyung Sik
通讯作者：
Kim, Hyung Sik
影响因子：
5.2
作者：
Wang, Jing;Kim, Tae Hyung;Kim, Hyung Sik
通讯作者：
Kim, Hyung Sik
影响因子：
5.7
作者：
Peck, Barrie;Chen, Chun-Yuan;Lam, Eric W. -F.
通讯作者：
Lam, Eric W. -F.