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Published on: November 23, 2016
Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6
Nan Qiu1, Daniel Abegg1, Mara Guidi2
1Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
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.
Insights
Artemisinin inhibits protein S-palmitoylation by targeting ZDHHC6, a key enzyme in cancer. This reduces oncogenic NRas palmitoylation, disrupting cancer cell signaling and proliferation.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Protein S-palmitoylation is a critical post-translational modification influencing protein function and localization in cancer.
- Oncoproteins and tumor suppressor proteins are regulated by S-palmitoylation, impacting cancer cell behavior.
Purpose of the Study:
- To identify novel inhibitors of protein S-palmitoylation in cancer cells.
- To investigate the anticancer mechanisms of artemisinin (ART).
Main Methods:
- Chemoproteomic screening to identify ZDHHC6 inhibitors.
- Biochemical assays to confirm ART's covalent binding and inhibition of ZDHHC6.
- Analysis of NRas palmitoylation, subcellular localization, and downstream signaling.
Main Results:
- Artemisinin (ART) was identified as a potent inhibitor of ZDHHC6, an endoplasmic reticulum-resident palmitoyl transferase.
- ART covalently binds and inhibits ZDHHC6, leading to reduced S-palmitoylation of the oncogenic protein NRas.
- Inhibition of NRas palmitoylation by ART disrupts its subcellular localization and attenuates pro-proliferative signaling cascades.
Conclusions:
- Artemisinin is a novel, non-lipid-based inhibitor of ZDHHC6, a specific palmitoyl acyltransferase.
- ART's inhibition of ZDHHC6 and subsequent NRas modification provides mechanistic insight into its anticancer activity.
- These findings support the ongoing clinical investigation of artemisinins for cancer therapy.
