title: Selenium suppresses leukemia through the action of endogenous eicosanoids.
abstract: Eradicating cancer stem-like cells (CSC) may be essential to fully eradicate cancer. Metabolic changes in CSC could hold a key to their targeting. Here, we report that the dietary micronutrient selenium can trigger apoptosis of CSC derived from chronic or acute myelogenous leukemias when administered at supraphysiologic but nontoxic doses. In leukemia CSC, selenium treatment activated ATM-p53-dependent apoptosis accompanied by increased intracellular levels of reactive oxygen species. Importantly, the same treatment did not trigger apoptosis in hematopoietic stem cells. Serial transplantation studies with BCR-ABL-expressing CSC revealed that the selenium status in mice was a key determinant of CSC survival. Selenium action relied upon the endogenous production of the cyclooxygenase-derived prostaglandins Δ(12)-PGJ2 and 15d-PGJ2. Accordingly, nonsteroidal anti-inflammatory drugs and NADPH oxidase inhibitors abrogated the ability of selenium to trigger apoptosis in leukemia CSC. Our results reveal how selenium-dependent modulation of arachidonic acid metabolism can be directed to trigger apoptosis of primary human and murine CSC in leukemia.
authors.affiliation: Authors' Affiliations: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania; and.
authors.forename: Ujjawal H
authors.initials: UH
authors.lastname: Gandhi
authors.affiliation: Authors' Affiliations: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania; and.
authors.forename: Naveen
authors.initials: N
authors.lastname: Kaushal
authors.affiliation: Authors' Affiliations: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania; and.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Hegde
authors.affiliation: Authors' Affiliations: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania; and.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Finch
authors.affiliation: Authors' Affiliations: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania; and.
authors.forename: Avinash K
authors.initials: AK
authors.lastname: Kudva
authors.affiliation: Authors' Affiliations: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania; and.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Kennett
authors.affiliation: Division of Hematology, Hematologic Malignancies, and Stem Cell Transplantation, University of Colorado, Anshutz Medical Campus, Aurora, Colorado.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: Authors' Affiliations: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania; and ksp4@psu.edu rfp5@psu.edu.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Paulson
authors.affiliation: Authors' Affiliations: Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania; and ksp4@psu.edu rfp5@psu.edu.
authors.forename: K Sandeep
authors.initials: KS
authors.lastname: Prabhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012643:Selenium / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013163:Splenomegaly; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D015777:Eicosanoids; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D003577:Cytochrome P-450 Enzyme System; D012643:Selenium