title: Arsenic inhibits autophagic flux, activating the Nrf2-Keap1 pathway in a p62-dependent manner.
abstract: The Nrf2-Keap1 signaling pathway is a protective mechanism promoting cell survival. Activation of the Nrf2 pathway by natural compounds has been proven to be an effective strategy for chemoprevention. Interestingly, a cancer-promoting function of Nrf2 has recently been observed in many types of tumors due to deregulation of the Nrf2-Keap1 axis, which leads to constitutive activation of Nrf2. Here, we report a novel mechanism of Nrf2 activation by arsenic that is distinct from that of chemopreventive compounds. Arsenic deregulates the autophagic pathway through blockage of autophagic flux, resulting in accumulation of autophagosomes and sequestration of p62, Keap1, and LC3. Thus, arsenic activates Nrf2 through a noncanonical mechanism (p62 dependent), leading to a chronic, sustained activation of Nrf2. In contrast, activation of Nrf2 by sulforaphane (SF) and tert-butylhydroquinone (tBHQ) depends upon Keap1-C151 and not p62 (the canonical mechanism). More importantly, SF and tBHQ do not have any effect on autophagy. In fact, SF and tBHQ alleviate arsenic-mediated deregulation of autophagy. Collectively, these findings provide evidence that arsenic causes prolonged activation of Nrf2 through autophagy dysfunction, possibly providing a scenario similar to that of constitutive activation of Nrf2 found in certain human cancers. This may represent a previously unrecognized mechanism underlying arsenic toxicity and carcinogenicity in humans.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, USA.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Lau
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Shasha
authors.initials: S
authors.lastname: Tao
authors.forename: Huihui
authors.initials: H
authors.lastname: Wang
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Whitman
authors.forename: Eileen
authors.initials: E
authors.lastname: White
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001151:Arsenic / Q000494:pharmacology* / Q000633:toxicity; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D017879:Isothiocyanates; D000072019:Kelch-Like ECH-Associated Protein 1; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000139:chemically induced; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C490981:Gtf2h1 protein, mouse; D006873:Hydroquinones; D017879:Isothiocyanates; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D034741:RNA, Small Interfering; D013454:Sulfoxides; D013861:Thiocyanates; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; C018855:2-tert-butylhydroquinone; C016766:sulforaphane; D001151:Arsenic