title: Zinc at sub-cytotoxic concentrations induces heme oxygenase-1 expression in human cancer cells.
abstract: OBJECTIVE
  This study investigated the effects of zinc on heme oxygenase-1 (HO-1) expression in human cancer cells.
  
  
  RESULTS
  Zinc at sub-cytotoxic concentrations (50-100 μM) induces HO-1 expression in the MDA-MB-231 (human breast cancer) and A2780 (human ovarian cancer) cell lines in a concentration- and time-dependent manner. The induction of HO-1 by zinc was detected after 4-6 hours of treatment, reached maximal level at 8 hours, and declined thereafter. Using a human HO-1 gene promoter reporter construct, we identified two antioxidant response elements (AREs) that mediated the zinc-induced increase in HO-1 gene transcription, indicating that the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway is involved in this event. This assumption was supported by the observations that knockdown of Nrf2 expression compromised the zinc-induced increase in HO-1 gene transcription, and that zinc increased Nrf2 protein expression and the Nrf2 binding to the AREs. Additionally, we found that the zinc-induced HO-1 gene transcription can be enhanced by clioquinol, a zinc ionophore, and reversed by pretreatment with TPEN, a known zinc chelator, indicating that an increase in intracellular zinc levels is responsible for this induction.
  
  
  CONCLUSIONS
  These findings demonstrate that zinc at sub-cytotoxic concentrations induces HO-1 expression in human cancer cells. The biological significance of this induction merits further investigation.
authors.affiliation: School of Radiation Medicine and Protection, Soochow University, Suzhou, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Jinchang
authors.initials: J
authors.lastname: Wu
authors.forename: Bethany N
authors.initials: BN
authors.lastname: Hannafon
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Ding
mesh_terms: D045744:Cell Line, Tumor; D007464:Clioquinol / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects*; D015032:Zinc / Q000633:toxicity*
chemical_list: D005029:Ethylenediamines; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D047493:PPAR alpha; D034741:RNA, Small Interfering; D007464:Clioquinol; D051547:Heme Oxygenase-1; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine