Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6.

Abstract

Protein S-palmitoylation is a post-translational modification that plays a crucial role in cancer cells by regulating the function and localization of oncoproteins and tumor suppressor proteins. Here, we identify artemisinin (ART), a clinically approved antimalarial endoperoxide natural product with promising anticancer activities, as an inhibitor of the ER-residing palmitoyl transferase ZDHHC6 in cancer cells using a chemoproteomic approach. We show that ART covalently binds and inhibits ZDHHC6 to reduce palmitoylation of the oncogenic protein NRas, disrupt NRas subcellular localization, and attenuate the downstream pro-proliferative signaling cascades. Our study identifies artemisinin as a non-lipid-based palmitoylation inhibitor targeting a specific palmitoyl acyltransferase and provides valuable mechanistic insights into the anticancer activity of artemisinins that are currently being studied in human clinical trials for different cancers.

• Authors: Nan Qiu, Daniel Abegg, Mara Guidi, Kerry Gilmore, Peter H Seeberger, Alexander Adibekian
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 29 Issue 3 Pg. 530-537.e7 (03 17 2022) ISSN: 2451-9448 [Electronic] United States
• PMID: 34358442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Artemisinins
• Membrane Proteins
• ZDHHC6 protein, human
• artemisinin
• Acyltransferases
• Acetyltransferases
• protein acyltransferase
• GTP Phosphohydrolases
• NRAS protein, human

Topics

• Acetyltransferases
• Acyltransferases (genetics)
• Artemisinins (pharmacology)
• GTP Phosphohydrolases
• Humans
• Lipoylation
• Membrane Proteins (genetics)
• Protein Processing, Post-Translational