Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells
Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells
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DOI：
10.1016/j.chembiol.2019.03.016
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发表时间：
2019-07-18
影响因子：
8.6
通讯作者：
Nomura, Daniel K.
中科院分区：
文献类型：
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作者：
Berdan, Charles A.;Ho, Raymond;Nomura, Daniel K.
银胶菊（Parthenopropylene）是一种来自小白菊属植物的天然产物，是倍半萜内酯大家族的成员，具有多种生物学和治疗活性，包括抗炎和抗癌作用。在这里，我们进一步研究了孤雌激素的作用机制，使用基于活性的蛋白质分析为基础的化学蛋白质组学平台，以映射在人类乳腺癌细胞中由孤雌激素参与的其他共价靶点。我们发现，小白菊，以及其他相关的环外含亚甲基内酯的倍半萜，共价修饰粘着斑激酶1（FAK1）的半胱氨酸427，导致FAK1依赖的信号通路和乳腺癌细胞增殖，存活和运动的损害。这些研究揭示了抗癌天然产物大家族成员利用的功能靶标。
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.