Dataset Information

Neocarzilin A is a potent inhibitor of cancer cell motility targeting VAT-1 controlled pathways

ABSTRACT: The natural product neocarzilin A (NCA) was discovered decades ago and despite its potent cytotoxic effects no mode of action studies were performed up to date. Synthesis of neocarzilins A, B, C and a stereoisomer of NCA provided insights into structural preferences as well as access to probes for functional studies. NCA pertained as the most active member and was not only effective against cell proliferation but also migration, a novel and so far overlooked activity. The potent anti-migratory effects could also be confirmed in an in vivo breast carcinoma mouse model. To decipher the molecular mode of action, we applied chemical proteomics for target discovery and revealed that NCA interrogates cancer cell migration via irreversible binding to the largely uncharacterized synaptic vesicle membrane protein VAT-1. A corresponding knockout of the protein confirmed the phenotype and pull-down studies showed the interaction with an intricate network of key migration mediators such as Talin-1. Overall, we introduce VAT-1 as a promising novel target for the development of selective migration inhibitors with the perspective to limit toxicity in absence of anti-proliferative effects.

INSTRUMENT(S): Orbitrap Fusion ETD, Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Liver Cancer,Breast Cancer

SUBMITTER: Carolin Gleissner

LAB HEAD: Stephan A. Sieber

PROVIDER: PXD012952 | Pride | 2019-08-23

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	100nMNC-1_desthiobiotin_enrichment_MDA-MB-231.zip	Other
	20151001_NC1_hepG2_108_1.raw	Raw
	20151001_NC1_hepG2_108_2.raw	Raw
	20151001_NC1_hepG2_108_3.raw	Raw
	20151001_NC1_hepG2_64_1.raw	Raw

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Publications

Neocarzilin A Is a Potent Inhibitor of Cancer Cell Motility Targeting VAT-1 Controlled Pathways.

Gleissner Carolin M-L CM Pyka Carolin L CL Heydenreuter Wolfgang W Gronauer Thomas F TF Atzberger Carina C Korotkov Vadim S VS Cheng Weiting W Hacker Stephan M SM Vollmar Angelika M AM Braig Simone S Sieber Stephan A SA

ACS central science 20190618 7

The natural product neocarzilin A (NCA) was discovered decades ago, and despite its potent cytotoxic effects no mode of action studies have been performed up to date. Synthesis of neocarzilins A, B, and C and a stereoisomer of NCA provided insights into structural preferences as well as access to probes for functional studies. NCA turned out to be the most active member and was not only effective against cell proliferation but also migration, a novel and so far overlooked ac ...[more]

PMID: 31403069

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