title: Inhibition of thioredoxin reductase by alantolactone prompts oxidative stress-mediated apoptosis of HeLa cells.
abstract: The mammalian thioredoxin reductase (TrxR) isoenzymes, TrxR1 in cytosol or nucleus, TrxR2 in mitochondria, and TrxR3 in testis, are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted increasing interests as potential targets for development of cancer chemotherapeutic agents. The sesquiterpene lactone alantolactone (ATL), an active component from the traditional folk medicine Inula helenium, has been documented possessing multiple pharmacological functions, especially the anticancer activity. However, the underlying mechanism has not been well defined. We reported that ATL inhibits both the recombinant TrxR and the enzyme in the cellular environment. The alpha-methylene-gamma-lactone moiety in ATL and the Sec residue in TrxR are critical for targeting TrxR by ATL. By employing our newly developed pull down assay, we demonstrated the remarkable elevation of the oxidized thioredoxin in HeLa cells after ATL treatment. In addition, ATL elicits accumulation of reactive oxygen species, and eventually induces apoptosis of HeLa cells. Importantly, overexpression of the functional TrxR attenuates the cytotoxicity of ATL, while knockdown of the enzyme sensitizes the cells to ATL treatment. Targeting TrxR thus discloses a novel molecular mechanism underlying the cellular action of ATL, and sheds light in considering the usage of ATL as a potential cancer chemotherapeutic agent.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
authors.forename: Junmin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 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 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 730000, China. Electronic address: npchem@lzu.edu.cn.
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China. Electronic address: fangjg@lzu.edu.cn.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Fang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D018922:HL-60 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D045787:Sesquiterpenes, Eudesmane / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; D045787:Sesquiterpenes, Eudesmane; D013880:Thioredoxin-Disulfide Reductase; C004363:alantolactone
keywords: Alantolactone; Alantolactone (PubChem CID: 72724); Apoptosis; Oxidative stress; Racemosalactone C (PubChem CID: 71665531); Redox regulation; Thioredoxin reductase