Molecular Probes Shed Light on Magnesium Homeostasis

项目摘要 镁水平调节参与糖酵解、克雷布斯循环和呼吸的酶的活性。 因此，有可能影响增加细胞增殖所需的代谢转化， 癌症的侵袭性和侵袭性。然而，镁稳态在癌症中的作用仍然是未知的。 深入研究，主要是由于缺乏有效的工具，用于检测细胞中的Mg 2+，而不受干扰 与其他生物相关的金属。例如，前列腺积聚高水平的二价 阳离子如Mg 2+、Zn 2+和Ca 2+，它们作为前列腺液的一部分与柠檬酸盐一起分泌， 需要适当的腺体功能。金属稳态的破坏被认为与 在从柠檬酸盐生产到柠檬酸盐氧化的代谢转变中，这是在肿瘤阶段之前， 前列腺恶性肿瘤的治疗。虽然在阐明其他人的作用方面取得了很大进展， 二价阳离子在这一过程中，镁在前列腺癌病因中的作用仍然是一个谜。在 在这个建议中，我们试图优化分子探针，以选择性地观察和定量镁 在干扰金属含量高的样品中，并利用新的工具来建立 前列腺细胞和组织中镁的积累与代谢活动和疾病前体的关系 格雷辛。这些研究代表了关键的第一步，以获得一个完整的图片的金属 前列腺和建立镁离子在代谢重编程相关的可能作用， 艾德得了癌症该项目的具体目标包括（i）开发用于可视化的最佳分子探针 和定量的细胞内镁2+在组织与高水平的干扰金属;（ii）映射的分布 前列腺组织样本中的Mg 2+和其他二价金属阳离子代表了不同阶段的前列腺增生， 状态恶性肿瘤;和（iii）研究细胞Mg 2+摄取与癌症代谢活性之间的相关性 细胞这些研究将为Mg 2+作为一种新的、迄今尚未探索的影响因素的作用提供新的见解。 代谢转化发生在前列腺癌的早期阶段。更深入地了解这种联系- 镁稳态和癌症进展之间的关系可能会导致新的治疗焦油的鉴定， 以阳离子运输为中心，并打开了使用金属水平作为生物标志物的大门， 为PCa和其他癌症提供新的诊断和监测工具。

PROJECT SUMMARY Magnesium levels modulate the activity of enzymes involved in glycolysis, the Krebs cycle, and the respira- tory chain; thus have the potential to influence the metabolic transformation required for increased cell prolifer- ation and invasiveness in cancer. The role of magnesium homeostasis in cancer, however, has remained un- derexplored, mainly due to the paucity of efficient tools for the detection of Mg2+ in cells without interference from other biologically–relevant metals. For example, the prostate gland accumulates high levels of divalent cations such as Mg2+, Zn2+ and Ca2+, which are secreted with citrate as part of the prostatic fluid and are re- quired for proper gland function. Disruption of metal homeostasis has been proposed to be intimately involved in the metabolic shift from citrate production to citrate oxidation that precedes the neoplastic stage in the de- velopment of prostate malignancies. Whereas much progress has been made on elucidating the role of other divalent cations in this process, the role of magnesium in the etiology of prostate cancer is still a mystery. In this proposal, we seek to optimize molecular probes for selective visualization and quantification of magnesium in samples with high levels of interfering metals, and to capitalize on the new tools to establish the patterns of magnesium accumulation in prostate cells and tissue in relationship with metabolic activity and disease pro- gression. These studies represent a critical first step toward obtaining a complete picture of the metallome of the prostate gland and establishing the possible role of Mg2+ cations in the metabolic reprogramming associat- ed with cancer. The specific aims of the project include (i) to develop optimal molecular probes for visualization and quantification of intracellular Mg2+ in tissues with high levels of interfering metals; (ii) to map the distribution of Mg2+ and other divalent metal cations in prostate tissue samples representative of different stages of pros- tate malignancy; and (iii) to study the correlation between cellular Mg2+ uptake with metabolic activity in cancer cells. These studies will offer new insight into the role of Mg2+ as a new, thus far unexplored factor influencing the metabolic transformation occurring in early stages of PCa. Deeper understanding of the connection be- tween magnesium homeostasis and cancer progression may lead to the identification of new therapeutic tar- gets centered in cation transport, and open the door to the use of metal levels as biomarkers for the develop- ment of novel diagnostic and surveillance tools for PCa and other cancers.