uL3 is a key regulator of oxidative stress response genes in multidrug resistant lung cancer cells

Lung cancer is one of the most common causes of cancer-related death among adults. Chemotherapy is recognized as an important component of treatment for all stages of lung cancer and is crucial in determining patient survival and quality of life. However, intrinsic or acquired multidrug resistance (MDR) is the main reason for tumor recurrence continuing to pose a significant challenge in the management of cancer. We previously reported evidence of the role of uL3 (formerly rpL3) in mediating drug resistance showing that the resistance of A549 lung cancer cells to Cisplatin correlates to the loss of uL3 expression. In this study we identified a key role of uL3 in the control of the redox status conferring multidrug resistance to lung cancer cells lacking p53. We established and characterized a multidrug resistant Calu-6 lung cell line. We found that uL3 down-regulation correlates positively with multidrug resistance. Restoration of the uL3 protein level re-sensitized the resistant cells to the drug by regulating the reactive oxygen species (ROS) levels, glutathione content, glutamate release, and cystine uptake. Chromatin immunoprecipitation experiments and luciferase assays demonstrated that uL3 coordinated the expression of stress-response genes acting as transcriptional repressors of solute carrier family 7 member 11 (xCT) and glutathione S-transferase α1 (GST-α1), independently of Nuclear factor erythroid 2-related factor 2 (Nrf2). Altogether our results describe a new function of uL3 as a regulator of oxidative stress response genes and advance our understanding of the molecular mechanisms underlying multidrug resistance in cancers. These data suggest the possibility of targeting uL3 to modulate the redox status of cancer cells for future therapeutic purposes in order to overcome MDR.