title: Shikonin targets cytosolic thioredoxin reductase to induce ROS-mediated apoptosis in human promyelocytic leukemia HL-60 cells.
abstract: Shikonin, a major active component of the Chinese herbal plant Lithospermum erythrorhizon, has been applied for centuries in traditional Chinese medicine. Although shikonin demonstrates potent anticancer efficacy in numerous types of human cancer cells, the cellular targets of shikonin have not been fully defined. We report here that shikonin may interact with the cytosolic thioredoxin reductase (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme with a C-terminal -Gly-Cys-Sec-Gly active site, to induce reactive oxygen species (ROS)-mediated apoptosis in human promyelocytic leukemia HL-60 cells. Shikonin primarily targets the Sec residue in TrxR1 to inhibit its physiological function, but further shifts the enzyme to an NADPH oxidase to generate superoxide anions, which leads to accumulation of ROS and collapse of the intracellular redox balance. Importantly, overexpression of functional TrxR1 attenuates the cytotoxicity of shikonin, whereas knockdown of TrxR1 sensitizes cells to shikonin treatment. Targeting TrxR1 with shikonin thus discloses a previously unrecognized mechanism underlying the biological activity of shikonin and provides an in-depth insight into the action of shikonin in the treatment of cancer.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
authors.forename: Dongzhu
authors.initials: D
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
authors.forename: Baoxin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China. Electronic address: fangjg@lzu.edu.cn.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Fang
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage* / Q000737:chemistry; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D009285:Naphthoquinones / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D004365:Drugs, Chinese Herbal; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; C016101:shikonin; D013880:Thioredoxin-Disulfide Reductase
keywords: Apoptosis; Free radicals; Reactive oxygen species; Redox; Shikonin; Thioredoxin reductase