Aldose Reductase Interacts With AKT1 To Augment Hepatic AKT/mTOR Signaling And To Promote Hepatocarcinogenesis

Background&Aims:A number of studies suggested aldose reductase(AR)as one of the most significantly up-regulated genes was associated with the development of hepatocellular carcinoma(HCC).Herein,we investigated how aberrantly overexpressed AR might promote oncogenic transformation in liver cells and tissues.Methods:The effects of AR overexpression and AR knockdown/knockout on AKT/mTOR signaling,lactate formation,the expression of KEAP1/NRF2 and TNFa/IL-6 were evaluated in vitro in cultured liver cancer cells and in vivo in the livers of human AR-overexpressing transgenics or Ar--deficient mice.Moreover,diethylnitrosamine-induced HCC was evaluated in vivo in the livers of AR-overexpressing transgenics or Ar-deficient mice.Results:Overexpression of AR was found to stabilize whereas knockdown of AR destabilized protein expression of AKT1/2,probably through an AR-AKT1 protein-protein interaction.Moreover,both enhancement and attenuation of the AR-AKT1 interaction caused dys-regulations in AKT/mTOR signaling,lactate formation,antioxidant defense signaling and inflammatory responses.In vivo in mice that were treated with diethylnitrosamine,livers-specific AR-overexpression in transgenics was found to promote whereas Ar deficiency in Ar-knockout mice was found to suppress diethylnitrosamine-induced HCC in part by modulating AKT/mTOR and antioxidant defense signaling,hepatic metabolic reprogramming and inflammatory responses.Conclusions:Aberrantly overexpressed hepatic AR interacts physically with AKT1,causing dys-regulations in AKT/mTOR signaling,metabolic reprogramming,antioxidative defense and inflammation,which tends to promote the development of HCC.Simultaneous inhibition of AR or AKT1 might serve as an effective strategy for the prevention and therapy of liver cancer.