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Involvement of Akt in mitomycin C and its analog triggered cytotoxicity in MCF‐7 and K562 cancer cells
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-09-11 , DOI: 10.1111/cbdd.13374
Shu-Yuan Cheng 1, 2 , Anayatzinc Vargas 1 , Ji-Young Lee 1 , Cristina C Clement 3, 4 , Elise Champeil 1
Affiliation  

Mitomycin C (MC) is a well‐known DNA alkylating agent. MC analog, 10‐decarbamoyl mitomycin C (DMC), unlike MC, has stronger effects on cancer with p53 mutation. We previously demonstrated that MC/DMC could activate p21WAF1/CIP1 in MCF‐7 (p53‐proficient) and K562 (p53‐deficient) cells in a p53‐independent mode. This study aimed to elucidate the upstream signaling pathway of p21WAF1/CIP1 activation triggered by MC/DMC. Besides p53, Akt plays an important role on deactivating p21WAF1/CIP1. The results showed that MC/DMC inhibited Akt in MCF‐7 cells, but not in K562 cells. By knocking down p53, the Akt inhibition in MCF‐7 cells was alleviated. This implied that the deactivated Akt caused by MC/DMC was p53‐dependent. With Akt activator (SC79), p21WAF1/CIP1 activation triggered by MC/DMC in MCF‐7 cells was not reduced. This indicated that Akt inhibition triggered by MC/DMC was not associated with MC/DMC‐induced p21WAF1/CIP1 activation. Label‐free quantitative proteomic profiling analysis revealed that DMC has a stronger effect on down‐regulating the PI3K/Akt signaling pathway in MCF‐7 cells as compared to MC. No significant effect of MC/DMC on PI3K/Akt in K562 cells was observed. In summary, MC/DMC regulate Akt activation in a p53‐dependent manner. This Akt deactivation is not associated with p21WAF1/CIP1 activation in response to MC/DMC.

中文翻译:


Akt 参与丝裂霉素 C 及其类似物引发 MCF-7 和 K562 癌细胞的细胞毒性



丝裂霉素 C (MC) 是一种众所周知的 DNA 烷化剂。 MC 类似物 10-去氨甲酰丝裂霉素 C (DMC) 与 MC 不同,对 p53 突变的癌症具有更强的作用。我们之前证明,MC/DMC 可以以 p53 独立模式激活 MCF-7(p53 丰富)和 K562(p53 缺陷)细胞中的 p21 WAF 1/ CIP 1 。本研究旨在阐明MC/DMC触发p21 WAF 1/ CIP 1激活的上游信号通路。除了 p53 之外,Akt 在使 p21 WAF 1/ CIP 1失活方面也发挥着重要作用。结果表明,MC/DMC 抑制 MCF-7 细胞中的 Akt,但不抑制 K562 细胞中的 Akt。通过敲低 p53,MCF-7 细胞中的 Akt 抑制得到缓解。这意味着 MC/DMC 引起的 Akt 失活是 p53 依赖性的。使用 Akt 激活剂 (SC79),MCF-7 细胞中 MC/DMC 触发的 p21 WAF 1/ CIP 1激活并未减少。这表明 MC/DMC 触发的 Akt 抑制与 MC/DMC 诱导的 p21 WAF 1/ CIP 1激活无关。无标记定量蛋白质组学分析表明,与 MC 相比,DMC 对 MCF-7 细胞中 PI3K/Akt 信号通路的下调作用更强。未观察到 MC/DMC 对 K562 细胞中 PI3K/Akt 的显着影响。总之,MC/DMC 以 p53 依赖性方式调节 Akt 激活。此 Akt 失活与响应 MC/DMC 的 p21 WAF 1/ CIP 1激活无关。
更新日期:2018-09-11
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