title: High basal nuclear levels of Nrf2 in acute myeloid leukemia reduces sensitivity to proteasome inhibitors.
abstract: Proteasome inhibitors such as bortezomib exhibit clinical efficacy in multiple myeloma, but studies in acute myeloid leukemia (AML) have been disappointing to date. The apparent failure in AML likely reflects a lack of biological understanding that might clarify applications of proteosome inhibitors in this disease. Here we show that AML cells are considerably less sensitive than control noncancerous cells to bortezomib-induced cytotoxicity, permitting most bortezomib-treated AML cells to survive treatment. We traced reduced bortezomib sensitivity to increased basal levels of nuclear Nrf2, a transcription factor that stimulates protective antioxidant enzymes. Bortezomib stimulates cytotoxicity through accumulation of reactive oxygen species (ROS) but elevated basal levels of nuclear Nrf2 present in AML cells reduced ROS levels, permitting AML cells to survive drug treatment. We further found that the Nrf2 transcriptional repressor Bach1 is rapidly inactivated by bortezomib, allowing rapid induction of Nrf2-regulated cytoprotective and detoxification genes that protect AML cells from bortezomib-induced apoptosis. By contrast, nonmalignant control cells lacked constitutive activation of Nrf2, such that bortezomib-mediated inactivation of Bach1 led to a delay in induction of Nrf2-regulated genes, effectively preventing the manifestation of apoptotic protection that is seen in AML cells. Together, our findings argue that AML might be rendered sensitive to proteasome inhibitors by cotreatment with either an Nrf2-inhibitory or Bach1-inhibitory treatment, rationalizing a targeted therapy against AML.
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich, United Kingdom.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Rushworth
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Bowles
authors.forename: David J
authors.initials: DJ
authors.lastname: MacEwan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D001897:Boronic Acids; D051856:Fanconi Anemia Complementation Group Proteins; D051267:NF-E2-Related Factor 2; D011719:Pyrazines; D017382:Reactive Oxygen Species; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex