Aldose reductase interacts with AKT1 to augment hepatic AKT/mTOR signaling and promote hepatocarcinogenesis.
Aldose reductase interacts with AKT1 to augment hepatic AKT/mTOR signaling and promote hepatocarcinogenesis.
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醛糖还原酶与 AKT1 相互作用增强肝脏 AKT/mTOR 信号传导并促进肝癌发生
DOI：
10.18632/oncotarget.17791
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Yang SY
中科院分区：
文献类型：
--
作者：
Zhao JX;Yuan YW;Cai CF;Shen DY;Chen ML;Ye F;Mi YJ;Luo QC;Cai WY;Zhang W;Long Y;Zeng Y;Ye GD;Yang SY
据报道，醛糖还原酶（AR）的显著上调与肝细胞癌（HCC）的发生相关。我们研究了异常过表达的AR如何促进肝细胞和组织的致癌转化。我们发现过表达的AR与AKT 1的激酶结构域相互作用，增加AKT/mTOR信号传导。在培养的肝癌细胞和DEN诱导的转基因HCC模型小鼠的肝组织中，我们观察到AR过表达诱导的AKT/mTOR信号倾向于增强乳酸盐形成和肝脏炎症，从而增强肝癌发生。相反，AR敲低抑制乳酸形成和炎症。使用培养的肝癌细胞，我们还证明了AKT 1对于AR诱导的AKT/mTOR信号转导、代谢重编程、抗氧化防御和炎症反应的失调是必不可少的。这些发现表明，异常过度表达/过度激活的肝AR至少部分通过与致癌AKT 1相互作用以增强AKT/mTOR信号传导来促进HCC的发展。抑制AR和/或AKT 1可能成为肝癌预防和治疗的有效策略。
Marked up-regulation of aldose reductase (AR) is reportedly associated with the development of hepatocellular carcinoma (HCC). We investigated how aberrantly overexpressed AR might promote oncogenic transformation in liver cells and tissues. We found that overexpressed AR interacted with the kinase domain of AKT1 to increase AKT/mTOR signaling. In both cultured liver cancer cells and liver tissues in DEN-induced transgenic HCC model mice, we observed that AR overexpression-induced AKT/mTOR signaling tended to enhance lactate formation and hepatic inflammation to enhance hepatocarcinogenesis. Conversely, AR knockdown suppressed lactate formation and inflammation. Using cultured liver cancer cells, we also demonstrated that AKT1 was essential for AR-induced dysregulation of AKT/mTOR signaling, metabolic reprogramming, antioxidant defense, and inflammatory responses. These findings suggest that aberrantly overexpressed/over-activated hepatic AR promotes HCC development at least in part by interacting with oncogenic AKT1 to augment AKT/mTOR signaling. Inhibition of AR and/or AKT1 might serve as an effective strategy for the prevention and therapy of liver cancer.
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