title: Role of uL3 in Multidrug Resistance in p53-Mutated Lung Cancer Cells.
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 inp53-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 glutathioneS-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.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131 Naples, Italy. annapina.russo@unina.it.
authors.forename: Annapina
authors.initials: A
authors.lastname: Russo
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131 Naples, Italy. assuntasaide@gmail.com.
authors.forename: Assunta
authors.initials: A
authors.lastname: Saide
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. silvia.smaldone@gmail.com.
authors.forename: Silvia
authors.initials: S
authors.lastname: Smaldone
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Via Sergio Pansini 5, 80131 Naples, Italy. raffaella.faraonio@unina.it.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Faraonio
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131 Naples, Italy. giulia.russo@unina.it.
authors.forename: Giulia
authors.initials: G
authors.lastname: Russo
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D027182:Amino Acid Transport System y+; D000970:Antineoplastic Agents; D007527:Isoenzymes; C000716547:RPL3 protein, human; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins; C118895:SLC7A11 protein, human; D016159:Tumor Suppressor Protein p53; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha
keywords: GST-α1; MDR1; Nrf2; chemoresistance; lung cancer; multidrug resistance; nucleolar stress; ribosomal protein; uL3; xCT