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Int. J. Mol. Sci. 2017, 18(3), 547; doi:10.3390/ijms18030547

Role of uL3 in Multidrug Resistance in p53-Mutated Lung Cancer Cells

1
Department of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano 49, 80131 Naples, Italy
2
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3
Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Via Sergio Pansini 5, 80131 Naples, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: Li Yang
Received: 18 January 2017 / Revised: 21 February 2017 / Accepted: 1 March 2017 / Published: 3 March 2017
(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)
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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. View Full-Text
Keywords: ribosomal protein; nucleolar stress; uL3; multidrug resistance; lung cancer; Nrf2; xCT; GST-α1; MDR1; chemoresistance ribosomal protein; nucleolar stress; uL3; multidrug resistance; lung cancer; Nrf2; xCT; GST-α1; MDR1; chemoresistance
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Russo, A.; Saide, A.; Smaldone, S.; Faraonio, R.; Russo, G. Role of uL3 in Multidrug Resistance in p53-Mutated Lung Cancer Cells. Int. J. Mol. Sci. 2017, 18, 547.

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