Targeting SLC7A11/xCT counteracts uL3mediated colorectal cancer drug resistance in 2D cell culture model and in ovo CAM xenograft

Despite advancements in therapeutic strategies, development of drug resistance remains a serious concern for the efficacy of chemotherapy against colorectal cancer (CRC). We have recently demonstrated that low expression of ribosomal protein uL3 positively correlates with chemoresistance and poor prognosis in CRC patients (previously published in: Carotenuto et al. (2023) Mol Pharm 20, 23262340). Here, we report the results of transcriptomic analysis that revealed a notable dysregulation of ferroptosisrelated genes in resistant uL3silenced CRC cells compared to the parental cells. Among them, SLC7A11 is one of the most dysregulated genes; specifically, its expression is inversely correlated with uL3 levels in resistant CRC cells and a large cohort of CRC patients. We demonstrated that uL3 downregulation in CRC cells promoted the upregulation of SLC7A11 at both posttranscriptional and posttranslational levels. Erastin, a pharmacological inhibitor of SLC7A11 function, impaired resistant uL3silenced CRC cell survival by inducing ferroptotic cell death as demonstrated by measurements of intracellular iron, glutathione, and reactive oxygen species levels as well as examination of key ferroptosisrelated markers. The antiproliferative and antimetastatic potential of erastin treatment was investigated in vivo by grafting treated uL3silenced CRC cells onto the chorioallantoic membrane (CAM). Overall, our study provides evidence of a novel therapeutic approach for sensitizing drugresistant CRCs overexpressing SLC7A11 and characterized by low levels of uL3.