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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, View ORCID ProfileDaniel K. Nomura
doi: https://doi.org/10.1101/550806
Charles A. Berdan
1Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720
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Raymond Ho
3Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720
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Haley S. Lehtola
1Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720
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Milton To
1Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720
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Xirui Hu
2Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720
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Tucker R. Huffman
2Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720
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Yana Petri
2Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720
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Chad R. Altobelli
2Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720
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Sasha G. Demeulenaere
2Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720
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James A. Olzmann
1Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720
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Thomas J. Maimone
2Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720
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  • For correspondence: maimone@berkeley.edu dnomura@berkeley.edu
Daniel K. Nomura
1Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720
2Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720
3Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720
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  • ORCID record for Daniel K. Nomura
  • For correspondence: maimone@berkeley.edu dnomura@berkeley.edu
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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.

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Posted February 14, 2019.
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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
bioRxiv 550806; doi: https://doi.org/10.1101/550806
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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
bioRxiv 550806; doi: https://doi.org/10.1101/550806

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