Aldose reductase interacts with AKT1 to augment hepatic AKT/mTOR signaling and promote hepatocarcinogenesis

• Published in: Oncotarget Vol. 8; no. 40; pp. 66987 - 67000
• Main Authors: Zhao, Jia-Xing, Yuan, Ya-Wei, Cai, Cheng-Fu, Shen, Dong-Yan, Chen, Mao-Li, Ye, Feng, Mi, Yan-Jun, Luo, Qi-Cong, Cai, Wang-Yu, Zhang, Wei, Long, Ying, Zeng, Yong, Ye, Guo-Dong, Yang, Shu-Yu
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 15.09.2017
• Subjects: Research Paper; aldose reductase; AKT/mTOR signaling; hepatocellular carcinoma
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.17791

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.