Abstract
Cancer is one of the most common causes of death among adults. Chemotherapy is crucial in determining patient survival and quality of life. However, the development of multidrug resistance (MDR) continues to pose a significant challenge in the management of cancer. In this study, we analyzed the role of human ribosomal protein uL3 (formerly rpL3) in multidrug resistance. Our studies revealed that uL3 is a key determinant of multidrug resistance in p53-mutated lung cancer cells by controlling the cell redox status. We established and characterized a multidrug resistant Calu-6 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.
Highlights
Lung cancer is one of the most common causes of cancer-related death among adults [1]
We demonstrated that upon ribosomal stress induced by 5-FU, ribosome free uL3 becomes a regulator of p21 [19,20], cystathionine-β-synthase (CBS) [21,22,23], and NFκB [22] expression and mediates apoptosis through the activation of the mitochondrial apoptotic response pathway
We have demonstrated that after drug treatment the ribosome-free uL3 behaves as a transcription factor [22], we became interested in determining if the uL3-mediated down-regulation of xCT and glutathione S-transferase α1 (GST-α1) expression occurred via the inhibition of gene transcription
Summary
Lung cancer is one of the most common causes of cancer-related death among adults [1]. We identified uL3 (formerly rpL3) as a key molecule conferring multidrug resistance to lung cancer cells lacking p53 and elucidated the molecular mechanism involved in this process. UL3 functions as a transcriptional regulator of solute carrier family 7 member 11 (xCT) and glutathione S-transferase α1 (GST-α1), independently of Nuclear factor erythroid 2-related factor 2 (Nrf). UL3 functions as a transcriptional regulator 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) These data imply that there is a mechanistic link between the response pathway to drug-induced ribosomal stress and the development of drug resistance and suggest the possibility of targeting uL3 to modulate the redox status of cancer cells for future therapeutic purposes in order to overcome MDR
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