Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer.
Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer.
复制标题
3-溴丙酮酸诱导结肠癌细胞死亡的机制
DOI：
10.1007/s10863-015-9612-1
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发表时间：
2015-08
影响因子：
3
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Sun Y;Liu Z;Zou X;Lan Y;Sun X;Wang X;Zhao S;Jiang C;Liu H
3-溴丙酮酸（3BP）是一种消耗能量的药物，通过糖酵解过程中的烷基化作用抑制己糖激酶II的活性，从而抑制ATP的产生并诱导细胞死亡。因此，3BP可以潜在地用作抗肿瘤剂。我们前期的研究表明3BP可以通过AKT /蛋白激酶B信号通路诱导乳腺癌细胞凋亡。在此，我们发现3BP也可以在同一时间和浓度下在SW 480和HT 29细胞系中通过坏死性凋亡和凋亡诱导结肠癌细胞死亡;在后者中，自噬也被发现是细胞死亡的机制。在HT 29细胞中，用3BP和自噬抑制剂3-甲基腺嘌呤（3-MA）的组合处理加剧了细胞死亡，而用半胱天冬酶抑制剂苄氧基羰基-Val-Ala-Asp氟甲基酮（z-VAD-factory）和坏死性凋亡抑制剂necrostatin（Nec）-1的伴随处理增强了3BP处理的细胞的活力。此外，3BP在SW 480异种移植小鼠模型中抑制肿瘤生长。这些结果表明，3BP可以通过多种机制抑制肿瘤生长并诱导细胞死亡，同时在不同类型的结肠癌细胞中通过消耗细胞能量储存来达到浓度。
3-Bromopyruvate (3BP) is an energy-depleting drug that inhibits Hexokinase II activity by alkylation during glycolysis, thereby suppressing the production of ATP and inducing cell death. As such, 3BP can potentially serve as an anti-tumorigenic agent. Our previous research showed that 3BP can induce apoptosis via AKT /protein Kinase B signaling in breast cancer cells. Here we found that 3BP can also induce colon cancer cell death by necroptosis and apoptosis at the same time and concentration in the SW480 and HT29 cell lines; in the latter, autophagy was also found to be a mechanism of cell death. In HT29 cells, combined treatment with 3BP and the autophagy inhibitor 3-methyladenine (3-MA) exacerbated cell death, while viability in 3BP-treated cells was enhanced by concomitant treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (z-VAD-fmk) and the necroptosis inhibitor necrostatin (Nec)-1. Moreover, 3BP inhibited tumor growth in a SW480 xenograft mouse model. These results indicate that 3BP can suppress tumor growth and induce cell death by multiple mechanisms at the same time and concentration in different types of colon cancer cell by depleting cellular energy stores.