The role of selenium in leukemia stem cell apoptosis
Open Access
- Author:
- Mccormick, Kayleigh M
- Area of Honors:
- Veterinary and Biomedical Sciences
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Dr. Kumble Sandeep Prabhu, Thesis Supervisor
Dr. Lester C Griel Jr., Thesis Honors Advisor - Keywords:
- selenium
leukemia stem cell
apoptosis
prostaglandins
15d-PGJ2
15-deoxy-Δ12
14-PGJ2
acute myeloid leukemia - Abstract:
- Selenium is an essential micronutrient that has important anti-inflammatory and anti-carcinogenic properties. Inflammatory stimuli upregulate the expression of cyclooxygenase-2 (COX-2), which increases the synthesis of inflammatory prostaglandins such as PGE2 as well as anti-inflammatory PGD2. The J-series prostaglandins, downstream metabolites of PGD2 have been shown to have anti-inflammatory and anti-tumorigenic properties, especially 15d-PGJ2. 15d-PGJ2 functions through multiple mechanisms, peroxisome proliferator activated receptor (PPAR)γ-dependent and independent, to induce apoptosis in cancerous cells, including Friend virus derived LSCs. We proposed that the anti-carcinogenic effects of Se are due to its upregulation of the terminal prostaglandin 15d-PGJ2. In order to test this hypothesis, a biologic assay for the production of 15d-PGJ2 in Se-supplemented cells was created. LPS-stimulated RAW 246.7 murine macrophages were grown under Se-supplemented or deficient conditions and treated with inhibitors of prostaglandin synthesis originating from AA metabolism, such as indomethacin, HQL-79, and CAY10526. Lipid extracts from these cells used to treat FV-LSCs induced apoptosis only in those samples that were Se-supplemented and endogenous production of 15d-PGJ2 was not inhibited, while the inhibition of PGE2 synthesis had no effect. Friend virus is a murine model of AML. The relapse rate for AML patients exceeds 80% because LSCs are highly resistant to conventional chemotherapy protocols. 15d-PGJ2 selectively induces apoptosis in LSCs. These preliminary studies suggest that upregulating 15d-PGJ2 synthesis by supplementing AML patients with Se is a promising therapeutic endpoint that is worth further investigation to pursue the potential chemotherapeutic and chemopreventive potential of Se.