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

TINGTING SUN, XUE SUN, XIN WANG, RUI GUO, YUANHUA YU*, LE GAO*

Changchun University of Science and Technology, Changchun, 130022, China

* Corresponding Authors: YUANHUA YU. Email: email; LE GAO. Email: email

(This article belongs to this Special Issue: Bioinformatics Study of Diseases)

BIOCELL 2023, 47(4), 879-889. https://doi.org/10.32604/biocell.2023.026229

Abstract

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)H-dependent oxidoreductases, plays a key role in the AKR-associated cis-platin resistance of HepG2 hepatic cancer cells.

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SUN, T., SUN, X., WANG, X., GUO, R., YU, Y. et al. (2023). Analysis of the mechanism of aldo-keto reductase dependent cis-platin resistance in HepG2 cells based on transcriptomic and NADH metabolic state. BIOCELL, 47(4), 879–889.



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