Abstract
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.
Highlights
Aldose reductase (EC1.1.1.21, AKR1B1, aldose reductase (AR)) is a member of the aldo-keto reductase (AKR) protein family, which plays important roles in nuclear receptor signaling, inflammatory responses, osmoregulation, endobiotic and xenobiotic detoxification, hormone synthesis and action, cellular metabolism and reproduction etc. [1]
Dozens of studies have reported that abnormal AKT1 activates in diabetes, cardiovascular diseases and various cancers [49,50,51]
In the present study we found that overexpressed AR interacted with AKT1 to increase protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling, which in turn promoted Warburg effects, lactate production, oxidative stress, and inflammation and contributed to hepatocarcinogenesis (Figures 1 and 4)
Summary
Aldose reductase (EC1.1.1.21, AKR1B1, AR) is a member of the aldo-keto reductase (AKR) protein family, which plays important roles in nuclear receptor signaling, inflammatory responses, osmoregulation, endobiotic and xenobiotic detoxification, hormone synthesis and action, cellular metabolism and reproduction etc. [1]. Consistent with the transcriptomic analyses, many proteomic studies indicated very significant elevations in the protein expression of AR and AKR1B10 in human liver cancer tissues [5, 7, 8, 12]. Some reports showed that AR/ AKR1B10 mRNA expression levels is an independent predictor of prognosis in HCC patients [10, 11]. In spite of these studies, very little studies were focus on the mechanism of the aberrantly overexpressed AR/ AKR1B10 contribute to the development or progression of various types of cancers
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