title: Activation of PPARγ by endogenous prostaglandin J2mediates the antileukemic effect of selenium in murine leukemia.
abstract: Supplementation with nontoxic doses of micronutrient selenium has been shown to alleviate chronic myelogenous leukemia (CML) via the elimination of leukemia stem cells (LSCs) in mice. This treatment provides a new and novel method for eliminating the LSCs that are otherwise not targeted by existing therapies. The antileukemic effect of selenium was dependent on the production of endogenous cyclopentenone prostaglandins (CyPGs), Δ-12 prostaglandin J2(Δ12-PGJ2), and 15-deoxy-Δ12,14-prostaglandin J2(15d-PGJ2). Here, we show that these endogenous CyPGs, produced by mice maintained on selenium-supplemented diets, alleviate the symptoms of CML through their ability to activate the nuclear hormone receptor, peroxisome proliferator activated receptor γ (PPARγ). GW9662, a potent PPARγ antagonist, blocked the antileukemic effect of selenium supplementation by significantly reducing CyPGs. This effect was mediated by an increase in 15-prostaglandin dehydrogenase (15-Pgdh) activity, which oxidizes and inactivates Δ12-PGJ2and 15d-PGJ2In contrast, treatment with the PPARγ agonist pioglitazone mimicked selenium supplementation. This treatment led to decreased 15-Pgdh activity and increased CyPG levels, which inhibited CML progression. Selenium-dependent activation of PPARγ mediated by endogenous CyPGs decreased Stat5 expression leading to the downregulation of Cited2, a master regulator of LSC quiescence. These studies suggest a potential role for selenium supplementation as an adjuvant therapy in CML.
authors.affiliation: Department of Veterinary and Biomedical Sciences.|Center for Molecular Immunology and Infectious Diseases, and.|Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Finch
authors.affiliation: Department of Veterinary and Biomedical Sciences.|Center for Molecular Immunology and Infectious Diseases, and.|Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA.
authors.forename: Diwakar B
authors.initials: DB
authors.lastname: Tukaramrao
authors.affiliation: Department of Veterinary and Biomedical Sciences.|Center for Molecular Immunology and Infectious Diseases, and.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Goodfield
authors.affiliation: Department of Veterinary and Biomedical Sciences.|Center for Molecular Immunology and Infectious Diseases, and.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Quickel
authors.affiliation: Department of Veterinary and Biomedical Sciences.|Center for Molecular Immunology and Infectious Diseases, and.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Paulson
authors.affiliation: Department of Veterinary and Biomedical Sciences.|Center for Molecular Immunology and Infectious Diseases, and.|Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA.
authors.forename: K Sandeep
authors.initials: KS
authors.lastname: Prabhu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D019587:Dietary Supplements; D007938:Leukemia / Q000188:drug therapy*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000502:physiology; D012643:Selenium / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C477819:15-deoxyprostaglandin J2; D000970:Antineoplastic Agents; D047495:PPAR gamma; C499810:delta(12)-prostaglandin J(2); C037112:9-deoxy-delta-9-prostaglandin D2; D012643:Selenium; D015230:Prostaglandin D2