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Neocarzilin inhibits cancer cell proliferation via BST-2 degradation resulting in lipid raft trapped EGFR

ABSTRACT: Neocarzilin (NCA) is a natural product exhibiting potent anti-migratory as well as anti-proliferative effects. While the vesicle amide 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 a second major target in cancer cells. The antiproliferative mechanism of NCA was confirmed in corresponding BST-2 knockout (KO) cells which were less sensitive to compound treatment. Vice versa, overexpression of the target in the KO reduced proliferation comparable to wild type (wt) cells. Whole proteome mass-spectrometric (MS) analysis of NCA treated wt and KO cancer cells unraveled affected pathways linked to EGFR signaling and demonstrated reduced levels of BST-2 upon NCA treatment. In-depth analysis of BST-2 levels in response to proteasome and lysosome inhibitors, confirmed a lysosomal degradation path upon NCA treatment. As BST-2 is mediating the release of EGFR from lipid rafts to turn on proliferation signaling pathways, reduced BST-2 levels led to attenuated phosphorylation of EGFR and downstream targets. Furthermore, fluorescence microscopy confirmed colocalization of BST-2 and lipid rafts in presence of NCA. Overall, NCA represents a versatile anti-cancer natural product with a unique dual mode of action and unconventional inhibition of proliferation via BST-2 degradation.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

DISEASE(S): Cervix Carcinoma,Breast Cancer

SUBMITTER: Josef Braun

LAB HEAD: Prof. Dr. Stephan Sieber

PROVIDER: PXD050453 | Pride | 2024-11-26

REPOSITORIES: Pride

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			Action	DRS
	20200930_uniprot-taxonomy__HomosapiensHuman9606_.fasta	Fasta
	20210602_JB_NC_138_1a_20210607200058.raw	Raw
	20210602_JB_NC_138_1b_20210608104553.raw	Raw
	20210602_JB_NC_138_1c_20210609013046.raw	Raw
	20210602_JB_NC_138_2a_20210607234217.raw	Raw

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Neocarzilin inhibits cancer cell proliferation via BST-2 degradation resulting in lipid raft trapped EGFR

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