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http://dx.doi.org/10.18419/opus-14589
Autor(en): | Braun, Josef Hu, Yudong Jauch, Adrian T. Gronauer, Thomas F. Mergner, Julia Bach, Nina C. Traube, Franziska R. Zahler, Stefan Sieber, Stephan A. |
Titel: | Neocarzilin inhibits cancer cell proliferation via BST‑2 degradation, resulting in lipid raft-trapped EGFR |
Erscheinungsdatum: | 2024 |
Dokumentart: | Zeitschriftenartikel |
Seiten: | 1833-1840 |
Erschienen in: | JACS Au 4 (2024), S. 1833-1840 |
URI: | http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-ds-146086 http://elib.uni-stuttgart.de/handle/11682/14608 http://dx.doi.org/10.18419/opus-14589 |
ISSN: | 2691-3704 |
Zusammenfassung: | Neocarzilin (NCA) is a natural product exhibiting potent antimigratory as well as antiproliferative effects. While vesicle amine transport protein 1 (VAT-1) was previously shown to inhibit migration upon NCA binding, the molecular mechanisms responsible for impaired proliferation remained elusive. We here introduce a chemical probe closely resembling the structural and stereochemical features of NCA and unravel bone marrow stromal antigen 2 (BST-2) as one of the targets responsible for the antiproliferative effect of NCA in cancer cells. The antiproliferative mechanism of NCA was confirmed in corresponding BST-2 knockout (KO) HeLa cells, which were less sensitive to compound treatment. Vice versa, reconstitution of BST-2 in the KO cells again reduced proliferation upon NCA addition, comparable to that of wild-type (wt) HeLa cells. Whole proteome mass spectrometric (MS) analysis of NCA-treated wt and KO cancer cells revealed regulated pathways and showed reduced levels of BST-2 upon NCA treatment. In-depth analysis of BST-2 levels in response to proteasome and lysosome inhibitors unraveled a lysosomal degradation path upon NCA treatment. As BST-2 mediates the release of epidermal growth factor receptor (EGFR) from lipid rafts to turn on proliferation signaling pathways, reduced BST-2 levels led to attenuated phosphorylation of STAT3. Furthermore, fluorescence microscopy confirmed increased colocalization of EGFR and lipid rafts in the presence of NCA. Overall, NCA represents a versatile anticancer natural product with a unique dual mode of action and unconventional inhibition of proliferation via BST-2 degradation. |
Enthalten in den Sammlungen: | 03 Fakultät Chemie |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | |
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au4c00039.pdf | 4,32 MB | Adobe PDF | Öffnen/Anzeigen |
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