Reduction of arsenic-induced cytotoxicity through Nrf2/HO-1 signaling in HepG2 cells.
Our previous study indicated that Nrf2 is a key transcription factor in cellular defenses against inorganic arsenite (iAsIII). However, the role of heme oxygenase-1 (HO-1), which is regulated by Nrf2, in iAsIII-induced cytotoxicity is poorly understood. To address this issue, we examined the contribution of HO-1 to iAsIII-mediated Nrf2 activation and in protection against iAsIII cytotoxicity in HepG2 cells. Exposure of HepG2 cells to iAsIII (10 microM) caused persistent induction of HO-1 accompanied by prolonged Nrf2 activation, whereas siRNA-mediated knockdown of HO-1 decreased prolonged Nrf2 activation. Pretreatment with either HO-1 siRNA or HO inhibitor (tin protoporphyrin IX) significantly enhanced iAsIII-induced cytotoxicity. These results suggest that iAsIII-induced HO-1 appears, at least in part, to act as a positive feedback regulator of Nrf2 activation, thereby diminishing its cytotoxicity in HepG2 cells.
Abiko
Yumi
Y
Doctoral Program in Life System Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba.
Shinkai
Yasuhiro
Y
Sumi
Daigo
D
Kumagai
Yoshito
Y
D018053:Arsenites / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism / Q000502:physiology*; D011524:Protoporphyrins / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*
D018053:Arsenites; D051267:NF-E2-Related Factor 2; D011524:Protoporphyrins; D034741:RNA, Small Interfering; C028025:protoporphyrin IX; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C015001:arsenite