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

Authors
  • Pecoraro, Annalisa
  • Carotenuto, Pietro1, 2
  • Franco, Brunella1, 3
  • De Cegli, Rossella1
  • Russo, Giulia
  • Russo, Annapina
  • 1 (R.D.C.)
  • 2 The Institute of Cancer Research, Cancer Therapeutics Unit 15 Cotswold Road, Sutton, London SM2 5NG, UK
  • 3 Medical Genetics, Department of Translational Medical Sciences, University of Naples “Federico II”, Via Sergio Pansini 5, 80131 Naples, Italy
Type
Published Article
Journal
International Journal of Molecular Sciences
Publisher
MDPI AG
Publication Date
Mar 20, 2020
Volume
21
Issue
6
Identifiers
DOI: 10.3390/ijms21062143
PMID: 32244996
PMCID: PMC7139652
Source
PubMed Central
Keywords
License
Green

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 116p53−/− 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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