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Analysis of the mechanism of Aldo-keto reductase dependent cis-platin resistance in HepG2 based on transcriptomic and NADH metabolic analysis

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.