Aldose reductase interacts with AKT1 to augment hepatic AKT/ mTOR signaling and promote hepatocarcinogenesis
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Jia-Xing Zhao1,*, Ya-Wei Yuan2,*, Cheng-Fu Cai3,*, Dong-Yan Shen3, Mao-Li Chen4, Feng Ye3, Yan-Jun Mi3, Qi-Cong Luo3, Wang-Yu Cai5, Wei Zhang3, Ying Long6, Yong Zeng6, Guo-Dong Ye3 and Shu-Yu Yang3
1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361002, China
2State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, 361002, China
3The First Affiliated Hospital, Medical College, Xiamen University, Xiamen, Fujian, 361003, China
4School of Pharmaceutical Science, Xiamen University, Xiamen, Fujian, 361003, China
5Medical College, Xiamen University, Xiamen, Fujian, 361003, China
6Translational Medicine Center, Hunan Cancer Hospital, Changsha, Hunan, 410013, China
*These authors contributed equally to this work
Shu-Yu Yang, email: firstname.lastname@example.org
Guo-Dong Ye, email: email@example.com
Keywords: aldose reductase, AKT/mTOR signaling, hepatocellular carcinoma
Received: November 22, 2016 Accepted: April 25, 2017 Published: May 10, 2017
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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