Activation of PPARγ by endogenous prostaglandin J2 mediates the antileukemic effect of selenium in murine leukemia

Emily R. Finch, Diwakar B. Tukaramrao, Laura L. Goodfield, Michael D. Quickel, Robert F. Paulson, K. Sandeep Prabhu

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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), D-12 prostaglandin J2 (D12-PGJ2), and 15-deoxy-D12,14-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 g (PPARg). GW9662, a potent PPARg 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 D12-PGJ2 and 15d-PGJ2. In contrast, treatment with the PPARg 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 PPARg 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.

Original languageEnglish (US)
Pages (from-to)1802-1810
Number of pages9
JournalBlood
Volume129
Issue number13
DOIs
StatePublished - Mar 30 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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