Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Fuchs, R; Stracke, A; Holzmann, V; Luschin-Ebengreuth, G; Meier-Allard, N; Ebner, N; Lassacher, TM; Absenger-Novak, M; Fröhlich, E; Schittmayer, M; Cano Crespo, S; Palacin, M; Rinner, B; Birner-Gruenberger, R.
Prazosin induced lysosomal tubulation interferes with cytokinesis and the endocytic sorting of the tumour antigen CD98hc.
Biochim Biophys Acta Mol Cell Res. 2018; 1865(9):1211-1229
Doi: 10.1016/j.bbamcr.2018.06.006
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- Führende Autor*innen der Med Uni Graz
- Fuchs Robert
- Co-Autor*innen der Med Uni Graz
- Absenger-Novak Markus
- Birner-Grünberger Ruth
- Ebner Nadine
- Fröhlich Eleonore
- Rinner Beate
- Schittmayer-Schantl Matthias
- Stracke Anika
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Cell Survival - drug effects
- Cytokinesis - drug effects
- Endocytosis - drug effects
- Fusion Regulatory Protein 1, Heavy Chain - genetics
- Fusion Regulatory Protein 1, Heavy Chain - metabolism
- Gene Expression Regulation, Neoplastic - drug effects
- Gene Knockout Techniques -
- HEK293 Cells -
- Humans -
- K562 Cells -
- Lysosomes - drug effects
- Lysosomes - metabolism
- Neoplasms - drug therapy
- Neoplasms - genetics
- Neoplasms - metabolism
- Prazosin - pharmacology
- Protein Transport - drug effects
- Up-Regulation -
- Find related publications in this database (Keywords)
- Cancer
- CD98hc/4F2/SLC3A2
- Prazosin
- Lysosomes
- Lysomototropic agents
- Apoptosis