1. Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells
- Author
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Milton To, James A. Olzmann, Xirui Hu, Haley S. Lehtola, Thomas J. Maimone, Tucker R. Huffman, Yana Petri, Daniel K. Nomura, Chad R. Altobelli, Sasha G. Demeulenaere, Charles A. Berdan, and Raymond Ho
- Subjects
natural products ,Clinical Biochemistry ,Tanacetum parthenium ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Lactones ,0302 clinical medicine ,Cell Movement ,Drug Discovery ,2.1 Biological and endogenous factors ,Aetiology ,Cancer ,0303 health sciences ,Tumor ,PTK2 ,Activity-based proteomics ,3. Good health ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Molecular Medicine ,FAK1 ,Female ,medicine.symptom ,Signal transduction ,Development of treatments and therapeutic interventions ,Sesquiterpenes ,Signal Transduction ,Cell Survival ,parthenolide ,Motility ,Breast Neoplasms ,covalent ligands ,Biology ,Article ,Cell Line ,Focal adhesion ,03 medical and health sciences ,Cell Line, Tumor ,Breast Cancer ,medicine ,Humans ,Parthenolide ,ABPP ,Molecular Biology ,030304 developmental biology ,Cell Proliferation ,activity-based protein profiling ,Pharmacology ,Biological Products ,Natural product ,010405 organic chemistry ,chemoproteomics ,0104 chemical sciences ,chemistry ,Mechanism of action ,Focal Adhesion Protein-Tyrosine Kinases ,Focal Adhesion Kinase 1 ,Cancer cell ,Cancer research ,Cysteine - 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. Herein, we further study parthenolide mechanism of action using activity-based protein profiling (ABPP)-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 (C427) 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 novel functional target exploited by members of a large family of anticancer natural products.
- Published
- 2019