RT Journal Article SR Electronic T1 Analysis of the mechanism of Aldo-keto reductase dependent cis-platin resistance in HepG2 based on transcriptomic and NADH metabolic analysis JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.04.29.441897 DO 10.1101/2021.04.29.441897 A1 Tingting Sun A1 Xue Sun A1 Xin Wang A1 Rui Guo A1 Yuanhua Yu A1 Le Gao YR 2021 UL http://biorxiv.org/content/early/2021/07/13/2021.04.29.441897.abstract AB Aldo-keto oxidoreductase (AKR) inhibitors could reverse several cancer cells’ resistance to Cis-platin, but their role in resistance remains unclear. 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. Knockdown of AKR1Cs could increase Cis-platin sensitivity in HepG2-RC cells about two-fold. Interestingly, the AKR1C inhibitor meclofenamic acid could increase Cis-platin sensitivity of HepG2-RC cells about eight-fold, indicating that 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 increased NADH could be explained as a directly operating antioxidant to scavenge radicals induced by Cis-platin. We report here that NADH, which is produced by NAD(P)H-dependent oxidoreductases, plays a key role in the AKR-associated Cis-platin resistance of HepG2 hepatic cancer cells.Competing Interest StatementThe authors have declared no competing interest.