Analysis of the mechanism of aldo-keto reductase dependent cis-platin resistance in HepG2 cells based on transcriptomic and NADH metabolic state  

作　　者：TINGTING SUN XUE SUN XIN WANG RUI GUO YUANHUA YU LE GAO 

机构地区：[1]Changchun University of Science and Technology,Changchun,130022,China

出　　处：《BIOCELL》2023年第4期879-889,共11页生物细胞（英文）

基　　金：supported by the Science and Technology Development Plan Project of Jilin Province,China[20200708101YY];The Foundation of Jilin Province Science and Technology Department[20200801062GH].

摘　　要：Background:Aldo-keto oxidoreductase(AKR)inhibitors could reverse the resistance of several cancer cells to cis-platin,but their role in resistance remains unclear.Methods:We verified the difference of AKR1Cs expression by Western blot,RNA sequencing and qRT-PCR.The differences of AKR1Cs expression were analyzed and inferred.Use Assay of NADH and NAD^(+)content to verify the inference.The Docking experience was used to verify the affinity between MPA,MCFLA,MLS and AKR1C3.Results:Our RNA-seq results showed de novo NAD biosynthesis-related genes and NAD(P)H-dependent oxidoreductases were significantly upregulated in cis-platin-resistant HepG2 hepatic cancer cells(HepG2-RC cells)compared with HepG2 cells.At least 63 NAD(P)H-dependent reductase/oxidases were upregulated in HepG2-RC cells at least twofold.Knockdown of AKR1Cs could increase cis-platin sensitivity in HepG2-RC cells about two-fold.Interestingly,the AKR1C inhibitor meclofenamic acid could increase the cis-platin sensitivity of HepG2-RC cells about eight-fold,indicating that the knockdown of AKR1Cs only partially reversed the resistance.Meanwhile,the amount of total NAD and the ratio of NADH/NAD^(+)were increased in HepG2-RC cells compared with HepG2 cells.The ratio of NADH/NAD^(+)in HepG2-RC cells was almost seven-fold higher than in HepG2 or HL-7702 cells.Increased NADH expression could be explained as a directly operating antioxidant to scavenge cis-platin-induced radicals.Conclusion:We report here that NADH,which is produced by NAD(P)Hdependent oxidoreductases,plays a key role in the AKR-associated cis-platin resistance of HepG2 hepatic cancer cells.

关 键 词：Aldo-keto oxidoreductase CIS-PLATIN HepG2 NAD(P)H-dependent oxidoreductases RNA sequencing 

分 类 号：R730.5[医药卫生—肿瘤]