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      Role of uL3 in the Crosstalk between Nucleolar Stress and Autophagy in Colon Cancer Cells

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          Abstract

          The nucleolus is the site of ribosome biogenesis and has been recently described as important sensor for a variety of cellular stressors. In the last two decades, it has been largely demonstrated that many chemotherapeutics act by inhibiting early or late rRNA processing steps with consequent alteration of ribosome biogenesis and activation of nucleolar stress response. The overall result is cell cycle arrest and/or apoptotic cell death of cancer cells. Our previously data demonstrated that ribosomal protein uL3 is a key sensor of nucleolar stress activated by common chemotherapeutic agents in cancer cells lacking p53. We have also demonstrated that uL3 status is associated to chemoresistance; down-regulation of uL3 makes some chemotherapeutic drugs ineffective. Here, we demonstrate that in colon cancer cells, the uL3 status affects rRNA synthesis and processing with consequent activation of uL3-mediated nucleolar stress pathway. Transcriptome analysis of HCT 116 p53−/− cells expressing uL3 and of a cell sub line stably depleted of uL3 treated with Actinomycin D suggests a new extra-ribosomal role of uL3 in the regulation of autophagic process. By using confocal microscopy and Western blotting experiments, we demonstrated that uL3 acts as inhibitory factor of autophagic process; the absence of uL3 is associated to increase of autophagic flux and to chemoresistance. Furthermore, experiments conducted in presence of chloroquine, a known inhibitor of autophagy, indicate a role of uL3 in chloroquine-mediated inhibition of autophagy. On the basis of these results and our previous findings, we hypothesize that the absence of uL3 in cancer cells might inhibit cancer cell response to drug treatment through the activation of cytoprotective autophagy. The restoration of uL3 could enhance the activity of many drugs thanks to its pro-apoptotic and anti-autophagic activity.

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          Most cited references35

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          Rapamycin passes the torch: a new generation of mTOR inhibitors.

          Mammalian target of rapamycin (mTOR) is an atypical protein kinase that controls growth and metabolism in response to nutrients, growth factors and cellular energy levels, and it is frequently dysregulated in cancer and metabolic disorders. Rapamycin is an allosteric inhibitor of mTOR, and was approved as an immuno-suppressant in 1999. In recent years, interest has focused on its potential as an anticancer drug. However, the performance of rapamycin and its analogues (rapalogues) has been undistinguished despite isolated successes in subsets of cancer, suggesting that the full therapeutic potential of targeting mTOR has yet to be exploited. A new generation of ATP-competitive inhibitors that directly target the mTOR catalytic site display potent and comprehensive mTOR inhibition and are in early clinical trials.
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            The coordinate regulation of the p53 and mTOR pathways in cells.

            Cell growth and proliferation requires an intricate coordination between the stimulatory signals arising from nutrients and growth factors and the inhibitory signals arising from intracellular and extracellular stresses. Alteration of the coordination often causes cancer. In mammals, the mTOR (mammalian target of rapamycin) protein kinase is the central node in nutrient and growth factor signaling, and p53 plays a critical role in sensing genotoxic and other stresses. The results presented here demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy, a tumor suppression process. Moreover, the mechanisms by which p53 regulates mTOR involves AMP kinase activation and requires the tuberous sclerosis (TSC) 1/TSC2 complex, both of which respond to energy deprivation in cells. In addition, glucose starvation not only signals to shut down mTOR, but also results in the transient phosphorylation of the p53 protein. Thus, p53 and mTOR signaling machineries can cross-talk and coordinately regulate cell growth, proliferation, and death.
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              Autophagy and multidrug resistance in cancer

              Multidrug resistance (MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence. Therefore, combatting MDR is an important issue. Autophagy, a self-degradative system, universally arises during the treatment of sensitive and MDR cancer. Autophagy can be a double-edged sword for MDR tumors: it participates in the development of MDR and protects cancer cells from chemotherapeutics but can also kill MDR cancer cells in which apoptosis pathways are inactive. Autophagy induced by anticancer drugs could also activate apoptosis signaling pathways in MDR cells, facilitating MDR reversal. Therefore, research on the regulation of autophagy to combat MDR is expanding and is becoming increasingly important. We summarize advanced studies of autophagy in MDR tumors, including the variable role of autophagy in MDR cancer cells.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                20 March 2020
                March 2020
                : 21
                : 6
                : 2143
                Affiliations
                [1 ]Department of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano 49, 80131 Naples, Italy; annalisa.pecoraro@ 123456unina.it
                [2 ]Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei, 34, 80078 Pozzuoli, Naples, Italy; p.carotenuto@ 123456tigem.it (P.C.); franco@ 123456tigem.it (B.F.); decegli@ 123456tigem.it (R.D.C.)
                [3 ]The Institute of Cancer Research, Cancer Therapeutics Unit 15 Cotswold Road, Sutton, London SM2 5NG, UK
                [4 ]Medical Genetics, Department of Translational Medical Sciences, University of Naples “Federico II”, Via Sergio Pansini 5, 80131 Naples, Italy
                Author notes
                [* ]Correspondence: giulia.russo@ 123456unina.it (G.R.); annapina.russo@ 123456unina.it (A.R.); Tel.: +39-081-746-3074 (G.R.); +39-081-678414 (A.R.)
                [†]

                These authors contributed equally to the work.

                Author information
                https://orcid.org/0000-0002-6622-183X
                https://orcid.org/0000-0002-7509-3702
                Article
                ijms-21-02143
                10.3390/ijms21062143
                7139652
                32244996
                f4951731-968a-426b-a19f-678b47e13825
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 February 2020
                : 17 March 2020
                Categories
                Article

                Molecular biology
                cancer,chemotherapy,nucleolar stress,nucleolus,p53,ribosomal proteins,ul3,autophagy
                Molecular biology
                cancer, chemotherapy, nucleolar stress, nucleolus, p53, ribosomal proteins, ul3, autophagy

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