Targeting Leukemia Stem Cells with Dietary Selenium

说明(申请人提供)：硒(Se)以硒半胱氨酸的形式结合到硒蛋白中，具有抗癌、抗氧化和抗炎功能。根据我们正在进行的研究，在轻度高硒状态下，免疫细胞将花生四烯酸代谢转移到环氧合酶(COX)衍生的抗炎环戊酮前列腺素(CyPG)15d-PGJ2的产生上，而不是促炎PGE2和血栓素A2。许多研究表明，在乳腺癌、结肠癌和前列腺癌的啮齿动物模型中，高硒抑制了启动、促进和进展，促进了实体癌细胞的凋亡。然而，Se对肿瘤干细胞(CSC)的影响还有待研究，CSC具有自我更新、多潜能和强大的增殖能力，在发育过程中处于顶端。现有的治疗癌症的方法并不能根除CSCs，因此有助于许多癌症的复发。为了填补这一普遍存在的空白，我们建议在以下三个模型中检测膳食Se对白血病干细胞(LSC)增殖的影响：1)将表达融合癌蛋白BCR-ABL或MLL-AF9的造血干细胞(HSC)移植到C57BL/6小鼠的Sca1试剂盒GFP LSC，作为慢性粒细胞白血病(CML)和急性髓细胞白血病(AML)的模型，以及2)来自感染Friend白血病逆转录病毒-多核细胞增多症(AML)的Balb/c小鼠的M34 Sca1试剂盒LSC。根据令人信服的初步数据，COX抑制剂阻断体内Se依赖的白血病消融效果，我们假设膳食超生理学水平的Se增加内源性CyPG的产生，通过激活P53途径特异性靶向LSCs的凋亡。这一假说将在三个特定的目标中得到验证：1)研究高Se补充是否导致LSCs的消融；2)研究COX途径代谢产物在Se补充小鼠LSCs选择性靶向中的作用；3)阐明15d-PGJ2在Se补充小鼠LSCs凋亡中的机制。鉴于白血病患者血清硒水平降低以及服用非阿司匹林止痛药的成人白血病发病率较高的流行病学证据，我们的长期目标是了解白血病患者补充硒是否有益。 与公共卫生相关：该提案基于硒生物学中一个研究相对较少的领域，该领域研究了这种微量营养素在选择性根除白血病干细胞中的作用。在补硒条件下，将利用白血病干细胞移植和白血病消融三种成熟的小鼠模型，研究内源性前列腺素代谢产物的形成及其在根除白血病干细胞中的作用。

DESCRIPTION (provided by applicant): Selenium (Se) is incorporated into selenoproteins as selenocysteine to impart anti-cancer, antioxidant, and anti-inflammatory functions. Based on our ongoing studies, under marginally high Se status, immune cells shunt the arachidonic acid metabolism towards the production of cyclooxygenase (COX)-derived anti-inflammatory cyclopentenone prostaglandin (CyPG) 15d- PGJ2 rather than pro-inflammatory PGE2 and thromboxane A2. Many studies have shown that high Se inhibits the initiation, promotion, and progression in rodent models of breast, colon, and prostate cancer, where apoptosis of bulk cancer cells was enhanced. However, studies are yet to be done to understand the effect of Se on cancer stem cells (CSC), which occupy the apex of the developmental hierarchy with properties of self-renewal, multipotentiality, and strong proliferative capacity. Existing therapie to treat cancer do not eradicate the CSCs and thus, aid in the relapse of many cancers. To fill this pervasive gap, we propose to examine the effect of dietary Se on the proliferation of leukemia stem cells (LSC) in the following three models: 1) transplantation of Sca1+kit+GFP+LSCs from C57BL/6 mice transplanted with hematopoietic stem cells (HSC) that express the fusion oncoproteins BCR-ABL or MLL-AF9 as models of chronic myelogenous leukemia (CML) and AML, respectively, and 2) M34+Sca1+kit+ LSCs from Balb/c mice infected with Friend leukemia retrovirus-polycythemia, a model of acute myelogenous leukemia (AML). Based on the compelling preliminary data that COX inhibitors block the effect of Se-dependent ablation of leukemia in-vivo, we hypothesize that supraphysiological levels of dietary Se increases the production of endogenous CyPGs to specifically target LSCs to apoptosis by activating the p53 pathway. The hypothesis will be tested in three Specific Aims: 1) To examine if high Se supplementation causes the ablation of LSCs; 2) To examine the role of COX pathway metabolites in the selective targeting of LSCs in Se-supplemented mice, and 3) To delineate the mechanism of apoptosis of LSCs by 15d-PGJ2 in Se supplemented mice. Given the epidemiological evidence of lowered serum Se levels in leukemia patients as well as higher incidences of adult leukemia in individuals consuming non-aspirin analgesics, our long- term goal is to understand if Se supplementation of leukemia patients would be beneficial. PUBLIC HEALTH RELEVANCE: The proposal is based on a relatively understudied area in selenium biology that examines the role of this micronutrient in the selective eradication of leukemia stem cells. Under selenium supplemented conditions, the formation of endogenous prostaglandin metabolites and their role in the eradication of leukemia stem cells will be studied using transplantation of leukemia stem cells and ablation of leukemia in three well established murine models.