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Chemoproteomic Profiling Reveals that Anti-Cancer Natural Product Dankastatin B Covalently Targets Mitochondrial VDAC3

Authors :
Bridget P. Belcher
Paulo A. Machicao
Binqi Tong
Emily Ho
Julia Friedli
Brian So
Helen Bui
Yosuke Isobe
Thomas J. Maimone
Daniel K. Nomura
Source :
bioRxiv
Publication Year :
2023
Publisher :
Cold Spring Harbor Laboratory, 2023.

Abstract

Chlorinated gymnastatin and dankastatin alkaloids derived from the fungal strainGymnascella dankaliensishave been reported to possess significant anti-cancer activity but their mode of action is unknown. These members possess electrophilic functional groups that may undergo covalent bond formation with specific proteins to exert their biological activity. To better understand the mechanism of action of this class of natural products, we mapped the proteome-wide cysteine-reactivity of the most potent of these alkaloids, dankastatin B, using activitybased protein profiling chemoproteomic approaches. We identified a primary target of dankastatin B in breast cancer cells as cysteine C65 of the voltage-dependent anion selective channel on the outer mitochondrial membrane VDAC3. We demonstrated direct and covalent interaction of dankastatin B with VDAC3. VDAC3 knockdown conferred hyper-sensitivity to dankastatin B-mediated anti-proliferative effects in breast cancer cells indicating that VDAC3 was at least partially involved in the anti-cancer effects of this natural product. Our study reveals a potential mode of action of dankastatin B through covalent targeting of VDAC3 and highlight the utility of chemoproteomic approaches in gaining mechanistic understanding of electrophilic natural products.

Subjects

Subjects :
Article

Details

Database :
OpenAIRE
Journal :
bioRxiv
Accession number :
edsair.doi.dedup.....e8b21dcfcdb4248953ae2570b22c4526
Full Text :
https://doi.org/10.1101/2023.02.11.528139