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Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
Neocarzilin inhibits cancer cell proliferation via BST-2 degradation, resulting in lipid raft-trapped EGFR.
JACS Au 4, 1833-1840 (2024)
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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Antitumor Agents ; Biological Activity ; Mechanism Of Action ; Natural Products ; Proteomics; Tool
ISSN (print) / ISBN
2691-3704
e-ISSN
2691-3704
Zeitschrift
JACS Au
Quellenangaben
Band: 4,
Heft: 5,
Seiten: 1833-1840
Verlag
American Chemical Society (ACS)
Verlagsort
1155 16th St, Nw, Washington, Dc 20036 Usa
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
CF Metabolomics & Proteomics (CF-MPC)
Förderungen
China Scholarship Council (CSC)
China Scholarship Council
Deutsche Forschungsgemeinschaft(DFG)
Foundation of German Business
China Scholarship Council
Deutsche Forschungsgemeinschaft(DFG)
Foundation of German Business