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

Charles A Berdan; Raymond Ho; Haley S Lehtola; Milton To; Xirui Hu; Tucker R Huffman; Yana Petri; Chad R Altobelli; Sasha G Demeulenaere; James A Olzmann; Thomas J Maimone; Daniel K Nomura

doi:10.1016/j.chembiol.2019.03.016

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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biological Products
Breast Neoplasms / metabolism*
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Female
Focal Adhesion Kinase 1 / antagonists & inhibitors
Focal Adhesion Kinase 1 / metabolism*
Focal Adhesion Protein-Tyrosine Kinases
Humans
Lactones
Sesquiterpenes / metabolism*
Sesquiterpenes / pharmacology
Signal Transduction / drug effects
Tanacetum parthenium

Substances

Biological Products
Lactones
Sesquiterpenes
methylene-lactone
parthenolide
Focal Adhesion Kinase 1
Focal Adhesion Protein-Tyrosine Kinases
PTK2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding