The ATP-binding cassette transporter ABCB6 is induced by arsenic and protects against arsenic cytotoxicity.
Arsenic, an environmental carcinogen, remains a major public health problem. Arsenic damages biological systems through multiple mechanisms, including the generation of reactive oxygen species. ABCB6 is an ATP-binding cassette transporter that is highly expressed in cells resistant to arsenic. We have recently demonstrated that ABCB6 expression protects against cellular stressors. In the present study, we evaluated the significance of ABCB6 expression to arsenic toxicity both in mice and in cell culture. We show that sodium arsenite induces ABCB6 expression in a dose-dependent manner both in mice fed sodium arsenite in drinking water and in cells exposed to sodium arsenite in vitro. Arsenite-induced ABCB6 expression was transcriptionally regulated, but this induction was not mediated by the redox-sensitive transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2). We demonstrate that, in HepG2 and Hep3B cells, knockdown of ABCB6 expression using ABCB6-specific small interfering RNA sensitized the cells to arsenite toxicity. In contrast, stable overexpression of ABCB6 conferred a strong survival advantage toward arsenite-induced oxidative stress. Collectively, these results, obtained by both loss of function and gain of function analysis, suggest that ABCB6 expression in response to sodium arsenite might be an endogenous protective mechanism activated to protect cells against arsenite-induced oxidative stress.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Hemantkumar
H
Chavan
Mahitha
M
Oruganti
Partha
P
Krishnamurthy
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017670:Sodium Compounds / Q000633:toxicity*
C107991:ABCB6 protein, human; D018528:ATP-Binding Cassette Transporters; C514489:Abcb6 protein, mouse; D018053:Arsenites; D002274:Carcinogens, Environmental; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; C017947:sodium arsenite
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