Targeting Leukemia Stem Cells with Dietary Selenium

描述（由申请人提供）：硒（Se）作为硒半胱氨酸被纳入硒蛋白中，具有抗癌、抗氧化和抗炎功能。根据我们正在进行的研究，在微量高硒状态下，免疫细胞将花生四烯酸代谢转向产生环加氧酶（COX）衍生的抗炎环戊酮前列腺素（CyPG） 15d- PGJ2，而不是促炎的PGE2和血栓素A2。许多研究表明，高硒抑制乳腺癌、结肠癌和前列腺癌啮齿动物模型的发生、促进和进展，其中大块癌细胞的凋亡增强。然而，硒对肿瘤干细胞（cancer stem cells， CSC）的影响尚待研究。CSC处于细胞发育的顶端，具有自我更新、多潜能和强大的增殖能力。现有的治疗癌症的方法不能根除csc，因此，有助于许多癌症的复发。为了填补这一普遍的空白，我们建议在以下三种模型中研究膳食硒对白血病干细胞（LSC）增殖的影响：1)用表达融合癌蛋白BCR-ABL或MLL-AF9的造血干细胞（HSC）移植C57BL/6小鼠的Sca1+kit+GFP+LSCs分别作为慢性髓性白血病（CML）和AML模型，以及M34+Sca1+kit+ Balb/c小鼠感染Friend白血病逆转录病毒-红细胞增多症（AML）模型的LSCs。基于令人信服的初步数据，COX抑制剂阻断体内硒依赖性白血病消融的作用，我们假设饮食中硒的超生理水平通过激活p53通路增加内源性CyPGs的产生，从而特异性靶向LSCs凋亡。该假设将在三个具体目标中得到验证：1)检查高硒补充是否会导致LSCs消融；2)研究COX通路代谢物在硒补充小鼠LSCs选择性靶向中的作用；3)探讨15d-PGJ2对硒补充小鼠LSCs凋亡的作用机制。鉴于流行病学证据表明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，我们的长期目标是了解白血病患者补充硒是否有益。

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.