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Cell Chem Biol. 2019 Jul 18;26(7):1027-1035.e22. doi: 10.1016/j.chembiol.2019.03.016. Epub 2019 May 9.

Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells.

Author information

1
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, University of California, Berkeley, Berkeley, CA 94720, USA.
2
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
3
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
4
Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
5
Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, University of California, Berkeley, Berkeley, CA 94720, USA.
6
Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: maimone@berkeley.edu.
7
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: dnomura@berkeley.edu.

Abstract

Parthenolide, a natural product from the feverfew plant and member of the large family of sesquiterpene lactones, exerts multiple biological and therapeutic activities including anti-inflammatory and anti-cancer effects. Here, we further study the parthenolide mechanism of action using activity-based protein profiling-based chemoproteomic platforms to map additional covalent targets engaged by parthenolide in human breast cancer cells. We find that parthenolide, as well as other related exocyclic methylene lactone-containing sesquiterpenes, covalently modify cysteine 427 of focal adhesion kinase 1 (FAK1), leading to impairment of FAK1-dependent signaling pathways and breast cancer cell proliferation, survival, and motility. These studies reveal a functional target exploited by members of a large family of anti-cancer natural products.

KEYWORDS:

ABPP; FAK1; PTK2; activity-based protein profiling; chemoproteomics; covalent ligands; focal adhesion kinase 1; natural products; parthenolide

PMID:
31080076
PMCID:
PMC6756182
[Available on 2020-07-18]
DOI:
10.1016/j.chembiol.2019.03.016

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