title: Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Dongzhu
authors.initials: D
authors.lastname: Duan
authors.affiliation: From the State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 and.
authors.forename: Junmin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 and.
authors.forename: Juan
authors.initials: J
authors.lastname: Yao
authors.affiliation: From the State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 and.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 and fangjg@lzu.edu.cn.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Fang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D020903:Tanacetum parthenium / Q000737:chemistry; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000037:antagonists & inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D012717:Sesquiterpenes; D013481:Superoxides; C002669:parthenolide; D019255:NADPH Oxidases; C516124:TXNRD1 protein, human; C516127:TXNRD2 protein, human; D054481:Thioredoxin Reductase 1; D054482:Thioredoxin Reductase 2
keywords: apoptosis; oxidation-reduction (redox); oxidative stress; parthenolide; reactive oxygen species (ROS); thioredoxin reductase