EGF Protects Cells Against Dox-Induced Growth Arrest Through Activating Cyclin D1 Expression
EGF Protects Cells Against Dox-Induced Growth Arrest Through Activating Cyclin D1 Expression
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EGF 通过激活细胞周期蛋白 D1 表达来保护细胞免受 Dox 诱导的生长停滞
DOI：
10.1002/jcb.25134
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发表时间：
2015
影响因子：
4
通讯作者：
Xue Li-Xiang
中科院分区：
文献类型：
--
作者：
Yao Chun-Xia;Shi Jia-Chen;Ma Cai-Xia;Xiong Cheng-Juan;Song Yang-Liu;Zhang Shu-Feng;Zhang Shan-Feng;Zang Ming-Xi;Xue Li-Xiang
据报道，抗肿瘤药物多柔比星（Dox）通过加塔-4耗竭发挥其毒性作用，并且加塔-4的过表达逆转了Dox诱导的毒性和细胞凋亡;然而，确切的机制仍不清楚。在这项研究中，我们首次观察到EGF保护细胞免受Dox介导的生长停滞，G2/M期停滞和凋亡。此外，EGF表达在Dox处理的细胞中下调，而在加塔-4过表达的细胞中上调。利用真实的时间PCR和蛋白质印迹分析，我们发现细胞周期相关蛋白cyclin D1的表达在加塔-4沉默的细胞和Dox处理的细胞中被抑制，并且在加塔-4过表达的细胞和EGF处理的细胞中被增强。此外，EGF处理逆转了由加塔-4 RNAi或Dox介导的细胞周期蛋白D1的抑制表达。我们的研究结果表明，EGF作为Dox的下游靶点，可能参与了Dox的毒性作用，并通过调节cyclin D1的表达，参与了加塔-4对Dox毒性的保护作用，阐明了Dox毒性的新的分子机制，具有重要的临床意义。J.细胞。116：1755-1765，2015.© 2015威利期刊公司.
It has been reported that the antitumor drug doxorubicin (Dox) exerts its toxic effects via GATA‐4 depletion and that over‐expression of GATA‐4 reverses Dox‐induced toxicity and apoptosis; however, the precise mechanisms remain unclear. In this study, we observed, for the first time, that EGF protects cells against Dox‐mediated growth arrest, G2/M‐phase arrest, and apoptosis. Additionally, EGF expression was down‐regulated in Dox‐treated cells and up‐regulated in GATA‐4 over‐expressing cells. Utilizing real‐time PCR and western blotting analysis, we found that the expression of the cell cycle‐associated protein cyclin D1 was inhibited in GATA‐4‐silenced cells and Dox‐treated cells and was enhanced in GATA‐4 over‐expressing cells and EGF‐treated cells. Furthermore, EGF treatment reversed the inhibited expression of cyclin D1 that was mediated by GATA‐4 RNAi or Dox. Our results indicate that EGF, as a downstream target of Dox, may be involved in Dox‐induced toxicity as well as in the protective role of GATA‐4 against toxicity induced by Dox via regulating cyclin D1 expression, which elucidates a new molecular mechanism of Dox toxicity with important clinical implications. J. Cell. Biochem. 116: 1755–1765, 2015. © 2015 Wiley Periodicals, Inc.