Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells. Issue 7 (18th July 2019)

• Record Type: Journal Article
• Authors: Berdan, Charles A.; Ho, Raymond; Lehtola, Haley S.; To, Milton; Hu, Xirui; Huffman, Tucker R.; Petri, Yana; Altobelli, Chad R.; Demeulenaere, Sasha G.; Olzmann, James A.; Maimone, Thomas J.; Nomura, Daniel K.
• Is Part Of: Cell chemical biology. Volume 26:Issue 7(2019)
• Page Start: 1027
• Page End: 1035.e22
• Publication Date: 2019-07-18
• Subjects: parthenolide -- natural products -- chemoproteomics -- covalent ligands -- focal adhesion kinase 1 -- FAK1 -- PTK2 -- activity-based protein profiling -- ABPP; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2019.03.016
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Parthenolide covalently reacts with C427 of FAK1 to inhibit FAK1 activity Parthenolide impairs FAK1 signaling in breast cancer cells Other sesquiterpene lactone natural products also target FAK1 Abstract : 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.