@Article{biocell.2023.026229,
AUTHOR = {TINGTING SUN, XUE SUN, XIN WANG, RUI GUO, YUANHUA YU, LE GAO},
TITLE = {Analysis of the mechanism of aldo-keto reductase dependent cis-platin resistance in HepG2 cells based on transcriptomic and NADH metabolic state},
JOURNAL = {BIOCELL},
VOLUME = {47},
YEAR = {2023},
NUMBER = {4},
PAGES = {879--889},
URL = {http://www.techscience.com/biocell/v47n4/51788},
ISSN = {1667-5746},
ABSTRACT = {<b>Background:</b> Aldo-keto oxidoreductase (AKR) inhibitors could reverse the resistance of several cancer cells to cis-platin, but their role in resistance remains unclear.<b>Methods:</b> 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<sup>+</sup> content to verify the inference. The Docking experience was used to verify the affinity between MPA, MCFLA, MLS and AKR1C3.<b>Results:</b> Our RNA-seq results showed <i>de novo</i> 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 <i>AKR1Cs</i> 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 <i>AKR1Cs</i> only partially reversed the resistance. Meanwhile, the amount of total NAD and the ratio of NADH/NAD<sup>+</sup> were increased in HepG2-RC cells compared with HepG2 cells. The ratio of NADH/NAD<sup>+</sup> 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.<b>Conclusion:</b> 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.},
DOI = {10.32604/biocell.2023.026229}
}