Cystine/glutamate exchanger xCT plays a critical role in uL3-mediated drug resistance

The human ribosomal protein L3 (uL3) has been identified as a key sensor in the cell response to chemotherapeutic drugs in colorectal cancer (CRC) cells lacking active p53. We have previously demonstrated that downregulation of uL3 positively correlates with chemoresistance, inhibition of apoptosis, alteration of epithelial-mesenchymal transition program, increasing in cell migration and proliferation, enhancement of autophagy, and overexpression of drug transporters. In particular, uL3 is a key determinant of multidrug resistance by controlling the cell redox status. The cystine/glutamate exchanger xCT plays a major role in regulating cell fate via its key function in uptake of cystine for the synthesis of glutathione (GSH) to counter oxidative stress and suppress ferroptosis. To assess the role of xCT in uL3-mediated drug resistance we analyzed its expression profile and its activity in p53 deleted colorectal cancer cells (HCT 116p53-/-) and in a derivative resistant cell subline stably silenced for uL3 (uL3Δ HCT 116p53-/-). Specifically, we performed quantitative polymerase chain reaction (qPCR), immunoblotting analysis, ribosome profiling, mRNA and protein stability experiments. Taken together, our results indicate that the cystine/glutamate exchanger xCT plays a critical role in uL3-based drug resistance regulating GSH intracellular levels and cell redox homeostasis.