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Prazosin induced lysosomal tubulation interferes with cytokinesis and the endocytic sorting of the tumour antigen CD98hc.

Authors
  • Fuchs, Robert1
  • Stracke, Anika2
  • Holzmann, Viktoria3
  • Luschin-Ebengreuth, Gerfried2
  • Meier-Allard, Nathalie2
  • Ebner, Nadine2
  • Lassacher, Teresa Maria2
  • Absenger-Novak, Markus4
  • Fröhlich, Eleonore4
  • Schittmayer, Matthias5
  • Cano Crespo, Sara6
  • Palacin, Manuel6
  • Rinner, Beate7
  • Birner-Gruenberger, Ruth5
  • 1 Chair of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Heinrichstraße 31, 8010 Graz, Austria. Electronic address: [email protected] , (Austria)
  • 2 Chair of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Heinrichstraße 31, 8010 Graz, Austria. , (Austria)
  • 3 Chair of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Heinrichstraße 31, 8010 Graz, Austria; FH JOANNEUM - University of Applied Sciences, Alte Poststraße 149, 8020 Graz, Austria. , (Austria)
  • 4 Centre for Medical Research, Medical University of Graz, Stiftingtalstrasse 24, 8010 Graz, Austria. , (Austria)
  • 5 Research Unit Functional Proteomics and Metabolic Pathways, Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria; Omics Center Graz, BioTechMed-Graz, Stiftingtalstrasse 24, 8010 Graz, Austria. , (Austria)
  • 6 Institute for Research in Biomedicine (IRB-Barcelona), Barcelona Institute of Science and Technology (BIST), Department of Biochemistry and Molecular Biomedicine, University of Barcelona, and CIBERER, Parc Científic de Barcelona. Baldiri I Reixac 10-12, 08028 Barcelona, Spain. , (Spain)
  • 7 Biomedical Research, Medical University of Graz, Roseggerweg 48, 8036 Graz, Austria. , (Austria)
Type
Published Article
Journal
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher
Elsevier
Publication Date
Sep 01, 2018
Volume
1865
Issue
9
Pages
1211–1229
Identifiers
DOI: 10.1016/j.bbamcr.2018.06.006
PMID: 29909287
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The quinazoline based drug prazosin (PRZ) is a potent inducer of apoptosis in human cancer cells. We recently reported that PRZ enters cells via endocytosis and induces tubulation of the endolysosomal system. In a proteomics approach aimed at identifying potential membrane proteins with binding affinity to quinazolines, we detected the oncoprotein CD98hc. We confirmed shuttling of CD98hc towards lysosomes and upregulation of CD98hc expression in PRZ treated cells. Gene knockout (KO) experiments revealed that endocytosis of PRZ still occurs in the absence of CD98hc - suggesting that PRZ does not enter the cell via CD98hc but misroutes the protein towards tubular lysosomes. Lysosomal tubulation interfered with completion of cytokinesis and provoked endoreplication. CD98hc KO cells showed reduced endoreplication capacity and lower sensitivity towards PRZ induced apoptosis than wild type cells. Thus, loss of CD98hc does not affect endocytosis of PRZ and lysosomal tubulation, but the ability for endoreplication and survival of cells. Furthermore, we found that glutamine, lysomototropic agents - namely chloroquine and NH4Cl - as well as inhibition of v-ATPase, interfere with the intracellular transport of CD98hc. In summary, our study further emphasizes lysosomes as target organelles to inhibit proliferation and to induce cell death in cancer. Most importantly, we demonstrate for the first time that the intracellular trafficking of CD98hc can be modulated by small molecules. Since CD98hc is considered as a potential drug target in several types of human malignancies, our study possesses translational significance suggesting, that old drugs are able to act on a novel target. Copyright © 2018 Elsevier B.V. All rights reserved.

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