title: Proteasome inhibition induces both antioxidant and hb f responses in sickle cell disease via the nrf2 pathway.
abstract: Oxidant stress is implicated in the manifestations of sickle cell disease including hemolysis and vascular occlusion. Strategies to induce antioxidant response as well as Hb F (α2γ2) have the potential to ameliorate the severity of sickle cell disease. Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2) is a transcription factor that regulates antioxidant enzymes as well as γ-globin transcription. The Nrf2 in the cytoplasm is bound to its adapter protein Keap-1 that targets Nrf2 for proteasomal degradation, thereby preventing its nuclear translocation. We examined whether inhibiting the 26S proteasome using the clinically applicable proteasome inhibitors bortezomib and MLN 9708 would promote nuclear translocation of Nrf2, and thereby induce an antioxidant response and as well as Hb F in sickle cell disease. Proteasome inhibitors induced reactive oxygen species (ROS) and thereby increased Nrf2-dependent antioxidant enzyme transcripts, elevated cellular glutathione (GSH) levels and γ-globin transcripts as well as Hb F levels in the K562 cell line and also in erythroid burst forming units (BFU-E) generated from peripheral blood mononuclear cells of sickle cell disease patients. These responses were abolished by siRNA-mediated knockdown of Nrf2. Proteasome inhibitors, especially newer oral agents such as MLN9708 have the potential to be readily translated to clinical trials in sickle cell disease with the dual end points of antioxidant response and Hb F induction.
authors.affiliation: Jane Ann Nohl Division of Hematology .
authors.forename: Vinod
authors.initials: V
authors.lastname: Pullarkat
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Meng
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Tahara
authors.forename: Cage S
authors.initials: CS
authors.lastname: Johnson
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kalra
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015672:Erythroid Precursor Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D061988:Proteasome Inhibitors; D011719:Pyrazines; D017382:Reactive Oxygen Species; D000069286:Bortezomib; D005319:Fetal Hemoglobin; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: Antioxidant response; Hb F; nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 of Nrf2); proteasome inhibitors; reactive oxygen species (ROS); sickle cell disease