Duan Dongzhu, Zhang Junmin, Yao Juan, Liu Yaping, Fang Jianguo
From the State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 and the Shannxi Key Laboratory of Phytochemistry, Baoji University of Arts and Sciences, Baoji 721013, China.
From the State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 and.
J Biol Chem. 2016 May 6;291(19):10021-31. doi: 10.1074/jbc.M115.700591. Epub 2016 Mar 21.
Parthenolide (PTL), a major active sesquiterpene lactone from the herbal plant Tanacetum parthenium, has been applied in traditional Chinese medicine for centuries. Although PTL demonstrates potent anticancer efficacy in numerous types of malignant cells, the cellular targets of PTL have not been well defined. We reported here that PTL interacts with both cytosolic thioredoxin reductase (TrxR1) and mitochondrial thioredoxin reductase (TrxR2), two ubiquitous selenocysteine-containing antioxidant enzymes, to elicit reactive oxygen species-mediated apoptosis in HeLa cells. PTL selectively targets the selenocysteine residue in TrxR1 to inhibit the enzyme function, and further shifts the enzyme to an NADPH oxidase to generate superoxide anions, leading to reactive oxygen species accumulation and oxidized thioredoxin. Under the conditions of inhibition of TrxRs in cells, PTL does not cause significant alteration of cellular thiol homeostasis, supporting selective target of TrxRs by PTL. Importantly, overexpression of functional TrxR1 or Trx1 confers protection, whereas knockdown of the enzymes sensitizes cells to PTL treatment. Targeting TrxRs by PTL thus discloses an unprecedented mechanism underlying the biological activity of PTL, and provides deep insights to understand the action of PTL in treatment of cancer.
小白菊内酯（PTL）是草本植物小白菊中的一种主要活性倍半萜内酯，已在传统中药中应用了数百年。尽管PTL在多种恶性细胞中显示出强大的抗癌功效，但其细胞靶点尚未明确界定。我们在此报告，PTL与胞质硫氧还蛋白还原酶（TrxR1）和线粒体硫氧还蛋白还原酶（TrxR2）这两种普遍存在的含硒半胱氨酸抗氧化酶相互作用，从而在HeLa细胞中引发活性氧介导的细胞凋亡。PTL选择性地靶向TrxR1中的硒半胱氨酸残基以抑制酶功能，并进一步将该酶转变为NADPH氧化酶以产生超氧阴离子，导致活性氧积累和硫氧还蛋白氧化。在细胞中TrxRs受到抑制的条件下，PTL不会引起细胞巯基稳态的显著改变，这支持了PTL对TrxRs的选择性靶向作用。重要的是，功能性TrxR1或Trx1的过表达赋予细胞保护作用，而这些酶的敲低则使细胞对PTL处理敏感。因此，PTL靶向TrxRs揭示了PTL生物活性背后前所未有的机制，并为理解PTL在癌症治疗中的作用提供了深刻见解。
