Involvement of Akt in mitomycin C and its analog triggered cytotoxicity in MCF-7 and K562 cancer cells.
Involvement of Akt in mitomycin C and its analog triggered cytotoxicity in MCF-7 and K562 cancer cells.
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DOI：
10.1111/cbdd.13374
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发表时间：
2018-12
影响因子：
3
通讯作者：
Champeil E
中科院分区：
文献类型：
--
作者：
Cheng SY;Vargas A;Lee JY;Clement CC;Champeil E
丝裂霉素C(MC)是一种广为人知的DNA烷基化试剂。与MC不同的是，MC类似物10-脱氨基甲酰丝裂霉素C(DMC)对p53突变的癌症有更强的作用。我们先前的研究证明MC/DMC能够以非p53依赖的方式激活MCF-7(P53-熟练)和K562(P53-缺失)细胞中的p21WAF1/CIP1。本研究旨在阐明MC/DMC激活p21WAF1/CIP1的上游信号通路。除P53外，Akt在p21WAF1/CIP1失活中起重要作用。结果表明，MC/DMC对MCF-7细胞Akt有抑制作用，而对K562细胞无明显抑制作用。通过下调P53，可减轻Akt对MCF-7细胞的抑制作用。提示MC/DMC引起的Akt失活是P53依赖性的。Akt激活剂(SC79)不降低MC/DMC对MCF-7细胞p21WAF1/CIP1的激活作用。这表明MC/DMC对Akt的抑制作用与MC/DMC诱导的p21WAF1/CIP1激活无关。无标记定量蛋白质组分析显示，与MC相比，DMC在下调MCF-7细胞PI3K/Akt信号通路方面具有更强的作用。MC/DMC对K562细胞PI3K/Akt无明显影响。综上所述，MC/DMC以P53依赖的方式调节Akt的激活。这种Akt失活与响应MC/DMC的p21WAF1/CIP1激活无关。丝裂霉素C(MC)及其类似物10-脱氨酰丝裂霉素C(DMC)以P53依赖的方式抑制MCF-7细胞中AKT的活性。然而，在MCF-7细胞中，Akt的失活并不与MC和DMC反应中的p21激活相关。蛋白质组学分析表明，与MC相比，DMC对MCF-7细胞Akt蛋白表达的下调作用更强，而MC/DMC对K562细胞Akt信号转导通路无明显影响。
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 downregulating the PI3K/Akt signaling pathway in MCF-7 cells as compared with 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. Deactivation of AKT was observed in MCF-7 cells treated with mitomycin C (MC) and its analog 10-decarbamoyl mitomycin C (DMC) in a p53-dependent manner. However, deactivation of Akt did not associate with p21 activation in response to MC and DMC in MCF-7 cells. Proteomic profiling analysis showed that DMC has a stronger effect on downregulation of Akt protein expression in MCF-7 cells as compared with MC, while there is no effect of MC/DMC on Akt signaling pathway in K562 cells.
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影响因子：
8
作者：
Gorospe, M;Cirielli, C;Holbrook, NJ
通讯作者：
Holbrook, NJ
DOI：
10.1073/pnas.1019062108
发表时间：
2011-04-19
影响因子：
11.1
作者：
Jo, Hakryul;Lo, Pang-Kuo;Luo, Hongbo R.
通讯作者：
Luo, Hongbo R.
影响因子：
4.8
作者：
Li, Y;Dowbenko, D;Lasky, LA
通讯作者：
Lasky, LA
影响因子：
5.2
作者：
Cheng SY;Seo J;Huang BT;Napolitano T;Champeil E
通讯作者：
Champeil E
影响因子：
4.8
作者：
Alvarez-Tejado, M;Naranjo-Suárez, S;del Peso, L
通讯作者：
del Peso, L