uL3 loss sensitize resistant p53 deleted colon cancer cells to ferroptosis

Despite recent therapeutic advancements, the development of drug resistance and metastasis remains a major obstacle to the successful treatment of colorectal cancer (CRC). We have previously demonstrated that low expression of ribosomal protein uL3 positively correlates with drug resistance in CRC patients. Here, we demonstrated that the loss of uL3 increased the metastatic capacity of CRC cells in chick embryos. RNA-Seq data of a large cohort of CRC patients unveiled a significant dysregulation of 108 genes related to ferroptosis. Solute Carrier Family 7 Member 11 (SLC7A11) is one of the most dysregulated genes and its expression is inversely correlated with uL3 levels. Erastin-mediated inhibition of SLC7A11 reduced resistant uL3-silenced CRC cell survival by inducing ferroptosis. Of note, the combination of erastin plus uL3 increased the sensitivity of uL3-silenced CRC cells to erastin. The antimetastatic capacity of the combined treatment was evaluated in chick embryos. Overall, our study provides evidence of a novel therapeutic approach, erastin plus uL3, to induce ferroptosis, establishing individualized therapy by examining p53, uL3 and SLC7A11 profiles in tumors.