Increased Glutamine Consumption in Cisplatin-Resistant Cells Has a Negative Impact on Cell Growth.

The emergence of drug-resistant subclones remains the primary reason for tumor treatment failure. Some theories suggest that drug-resistant cell growth can be suppressed by drug-sensitive cells because resistant cells are less fit than sensitive cells in the absence of drug. We investigated fitness differences and their underlying mechanisms in cisplatin (ddp)-resistant cells and parental cells. We found that glutamine (Gln) consumption was substantially higher in ddp-resistant cells than that in sensitive cells, indicating that significantly fewer ddp-resistant cells than sensitive cells could be generated under the same Gln conditions. Interestingly, the antioxidant capacity of ddp-resistant cells was also significantly enhanced and was directly related to the presence of Gln. Then, we found that enhanced antioxidant capacity was sustained by accelerated Gln catabolism in resistant cells through oncogenic KRAS. Further analysis indicated that rapid Gln catabolism directly mediated ddp resistance through enhanced antioxidant capacity, but the maximum number of resistant cells that could be produced with the same amount of Gln was significantly reduced due to increased Gln catabolism. Collectively, our study revealed that rapid Gln catabolism provided ddp-resistant cells with the ability to tolerate cytotoxic treatment but also hindered the growth of ddp-resistant cells due to excessive Gln consumption.