Paclitaxel suppresses the viability of breast tumor MCF7 cells through the regulation of EF1α and FOXO3a by AMPK signaling
Paclitaxel suppresses the viability of breast tumor MCF7 cells through the regulation of EF1α and FOXO3a by AMPK signaling
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DOI：
10.3892/ijo.2015.3153
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发表时间：
2015-11-01
影响因子：
5.2
通讯作者：
Kim, Hyeon Soo
中科院分区：
文献类型：
--
作者：
Kim, Ji Hae;Lee, Jung Ok;Kim, Hyeon Soo
紫杉醇（Taxol）是一种从太平洋紫杉树皮中分离出来的天然强效药物，广泛用于治疗卵巢癌、肺癌和乳腺癌。目前，关于紫杉醇抗癌活性的具体机制的信息很少。在本研究中，我们发现5-氨基-1-β-D-呋喃核糖基咪唑-4-甲酰胺（AICAR），一种众所周知的腺苷一磷酸（AMP）激活蛋白激酶（AMPK）的激活剂，下调乳腺癌MCF 7细胞中延伸因子1 α（EF 1 α）的蛋白和mRNA水平。Paclitazone可增加MCF 7细胞AMPK的磷酸化水平，并下调EF 1 α的表达。此外，紫杉醇增加叉头框O3 a（FOXO 3a）的表达以及磷酸化。在化合物C（一种特异性AMPK抑制剂）存在下，FOXO 3a的磷酸化被抑制，表明AMPK参与紫杉醇诱导的FOXO 3a磷酸化。在EF 1 α和AMPK敲低细胞中未观察到紫杉醇对FOXO 3a的诱导和磷酸化：与AICAR共处理导致癌细胞对紫杉醇诱导的抑制其活力的敏感性增加，并进一步增强紫杉醇诱导的FOXO 3a磷酸化。这些结果表明，紫杉醇在乳腺癌中的抗肿瘤作用是通过激活AMPK/EF 1 α/FOXO 3a信号通路介导的。
Paclitaxel (Taxol), a potent drug of natural origin isolated from the bark of the Pacific yew, is widely used for treating ovarian, lung and breast cancers. Currently, there is little information regarding the specific mechanism underlying the anticancer activity of paclitaxel. In the present study, we found that 5-amino-1-beta-D-ribofuranosylimidazole-4-carboxamide (AICAR), a well-known activator of adenosine monophosphate (AMP)-activated protein kinase (AMPK), downregulated the protein and mRNA levels of elongation factor 1 alpha (EF1 alpha) in breast cancer MCF7 cells. Paclitaxel increased the phosphorylation of AMPK and also downregulated the expression of EF1 alpha in MCF7 cells. In addition, paclitaxel increased the expression, as well as the phosphorylation of forkhead box O3a (FOXO3a). Phosphorylation of FOXO3a was suppressed in the presence of compound C, a specific AMPK inhibitor, suggesting the involvement of AMPK in paclitaxel-induced FOXO3a phosphorylation. The induction and phosphorylation of FOXO3a by paclitaxel were not observed in EF1 alpha and AMPK knockdown cells: Co-treatment with AICAR resulted in increased susceptibility of cancer cells to paclitaxel-induced suppression of their viability and further enhanced paclitaxel-induced FOXO3a phosphorylation. These results suggest that the antitumor effects of paclitaxel in breast cancer are mediated by activation of the AMPK/EF1 alpha/FOXO3a signaling pathway.