P38 MAP kinase functions as a switch in MS-275-induced reactive oxygen species-dependent autophagy and apoptosis in Human colon Cancer cells
P38 MAP kinase functions as a switch in MS-275-induced reactive oxygen species-dependent autophagy and apoptosis in Human colon Cancer cells
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P38 MAP 激酶在人结肠癌细胞中 MS-275 诱导的活性氧依赖性自噬和细胞凋亡中充当开关
DOI：
10.1016/j.freeradbiomed.2012.05.018
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发表时间：
2012-08-01
影响因子：
7.4
通讯作者：
Li, Wenhua
中科院分区：
文献类型：
--
作者：
Zhan, Yao;Gong, Ke;Li, Wenhua
MS-275是组蛋白去乙酰化酶抑制剂的合成苯甲酰胺衍生物，目前处于I/II期临床试验中。许多报告表明，MS-275在几种类型的癌症中的抗肿瘤活性主要归因于其诱导肿瘤细胞凋亡的能力。目前尚不清楚自噬是否参与MS-275对癌细胞的治疗。在这里，我们首先表明，MS-275诱导人结肠癌细胞HCT 116自噬以及凋亡。短期处理（24 h）诱导HCT 116细胞经历依赖于细胞内活性氧产生和ERK激活的自噬。活化的活性氧/ERK信号促进Atg 7蛋白表达，从而触发MS-275诱导的癌细胞自噬。然而，MS-275长时间处理（超过48小时）后，自噬细胞凋亡，这也依赖于活性氧的产生。有趣的是，我们发现p38 MAP激酶在MS-275诱导的人结肠癌细胞从自噬到凋亡的转变中起着至关重要的作用。p38高表达可诱导细胞自噬，低表达可导致细胞凋亡。此外，体内观察结果与体外结果非常一致。因此，这些发现扩展了我们对MS-275诱导癌细胞死亡的作用的理解，并表明它可能是一种有前途的具有多种作用的临床化疗药物。(C)2012 Elsevier Inc. All rights reserved.
MS-275 is a synthetic benzamide derivative of the histone deacetylase inhibitor and is currently in phase I/II clinical trials. Many reports have shown that the anti-tumor activity of MS-275 in several types of cancer is mainly attributable to its capacity to induce the apoptotic death of tumor cells. It remains unclear if autophagy is involved in MS-275 treatment of cancer cells. Here, we first show that MS-275 induces human colon cancer cell HCT116 autophagy as well as apoptosis. Short-term treatment (24 h) induced HCT116 cells to undergo autophagy with dependence on intracellular reactive oxygen species production and ERK activation. The activated reactive oxygen species/ERK signal promoted Atg7 protein expression, which triggered MS-275-induced cancer cell autophagy. However, after prolonged treatment with MS-275 (over 48 h), autophagic cells turned apoptotic, which was also dependent on reactive oxygen species generation. Interestingly, we found that p38 MAP kinase played a vital role in the switch from autophagy to apoptosis in MS-275-induced human colon cancer cells. High expression of p38 induced cell autophagy, but low expression resulted in apoptosis. In addition, observations in vivo are strongly consistent with the in vitro results. Therefore, these findings extend our understanding of the action of MS-275 in inducing cancer cell death and suggest that it may be a promising clinical chemotherapeutic agent with multiple effects. (C) 2012 Elsevier Inc. All rights reserved.