3-Bromopyruvate induces apoptosis in breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway
3-Bromopyruvate induces apoptosis in breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway
复制标题
3-Bromopyruvate 通过 PI3K/Akt 信号通路下调 Mcl-1，诱导乳腺癌细胞凋亡。
DOI：
10.1097/cad.0000000000000081
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发表时间：
2014-04-01
影响因子：
2.3
通讯作者：
Liu, Hao
中科院分区：
文献类型：
--
作者：
Liu, Zhe;Zhang, Yuan-Yuan;Liu, Hao
己糖激酶抑制剂3-溴丙酮酸（3-BrPA）可以抑制肿瘤细胞的糖酵解，减少ATP的产生，导致细胞凋亡。然而，由于3-BrPA是一种烷化剂，其细胞毒性作用可能由其他分子机制诱导。结果表明3-BrPA诱导的细胞凋亡不依赖于caspase。此外，3-BrPA诱导MDA-MB-231细胞中活性氧物质的产生，导致细胞凋亡。这些结果表明，半胱天冬酶非依赖性细胞凋亡可能是由活性氧的产生诱导。在这项研究中，我们还证明了3-BrPA通过下调MDA-MB-231乳腺癌细胞中的髓样细胞白血病-1（Mcl-1）诱导细胞凋亡。Mcl-1基因敲低的结果表明，Mcl-1在3-BrPA诱导的细胞凋亡中起重要作用。此外，3-BrPA处理的MDA-MB-231细胞中Mcl-1表达的上调显著增加了细胞活力。此外，3-BrPA处理导致p-Akt的下调，表明3-BrPA可能通过磷酸肌醇-3-激酶/Akt途径下调Mcl-1。这些发现表明，3-BrPA通过磷酸肌醇-3-激酶/Akt信号通路下调Mcl-1诱导乳腺癌细胞凋亡。
The hexokinase inhibitor 3-bromopyruvate (3-BrPA) can inhibit glycolysis in tumor cells to reduce ATP production, resulting in apoptosis. However, as 3-BrPA is an alkylating agent, its cytotoxic action may be induced by other molecular mechanisms. The results presented here reveal that 3-BrPA-induced apoptosis is caspase independent. Further, 3-BrPA induces the generation of reactive oxygen species in MDA-MB-231 cells, leading to mitochondria-mediated apoptosis. These results suggest that caspase-independent apoptosis may be induced by the generation of reactive oxygen species. In this study, we also demonstrated that 3-BrPA induces apoptosis through the downregulation of myeloid cell leukemia-1 (Mcl-1) in MDA-MB-231 breast cancer cells. The results of Mcl-1 knockdown indicate that Mcl-1 plays an important role in 3-BrPA-induced apoptosis. Further, the upregulation of Mcl-1 expression in 3-BrPA-treated MDA-MB-231 cells significantly increases cell viability. In addition, 3-BrPA treatment resulted in the downregulation of p-Akt, suggesting that 3-BrPA may downregulate Mcl-1 through the phosphoinositide-3-kinase/Akt pathway. These findings indicate that 3-BrPA induces apoptosis in breast cancer cells by downregulating Mcl-1 through the phosphoinositide-3-kinase/Akt signaling pathway.