Understanding the mechanisms of iron addiction in colon cancer

摘要 如果及早发现，结直肠癌(CRC)可以得到有效的治疗。然而，大多数肿瘤是在 治疗选择有限的晚期。评估变更的情况又重新出现了 癌细胞生长过程中的细胞代谢。与正常细胞不同，癌细胞主要依赖有氧糖酵解来获得三磷酸腺苷 制作。有氧糖酵解在ATP的生成中效率低下，但糖酵解和TCA循环 中间产物被改道以生产生物质。这些研究已经确定了几个 有可能成为治疗靶点的关键途径。目前，人们对这一事件知之甚少 微量营养素代谢在癌症中的作用。我们最近的研究表明，铁的积累 是结肠癌生长和发展的关键一步。结肠癌细胞对高铁上瘾 细胞增殖水平。我们已经清楚地表明，肿瘤内有铁的积聚。 与邻近正常粘膜相比。遗传或饮食限制会导致铁的显著减少。 肿瘤的增殖和进展。然而，目前还不清楚癌细胞是如何维持高铁水平的。 抵抗铁介导的氧化毒性，并利用铁信号、生存和生长。我们的目标是 找出这些主要缺口背后的机制，为以铁为基础的结肠治疗奠定基础 癌症。我们假设CRCs绕过了高铁蓄积的毒性，从而促进了肿瘤的发生。 发信号。细胞铁水平受一种肝脏激素海普西丁的调节。海普西丁与铁结合 出口商铁蛋白导致铁的降解和抑制铁的出口。我们发现结肠肿瘤 上皮细胞表达高水平的海普西丁和低水平的铁蛋白。目标1将描述海普西丁/铁转移蛋白 AXIS是导致铁蓄积的主要机制，是否可以靶向治疗。铁是 对生长是必不可少的，但对细胞可能有很高的毒性。铁的水平需要严格控制。通过熨斗熨烫 Fenton反应导致高超氧化物的形成，并引发一种称为 铁性下垂。我们最近的数据表明，CRCs可以有效地抑制铁性下垂。Aim 2会理解的 导致铁诱导损伤的抗性机制。在目标3中，我们将解决为什么CRC需要高 维持生长所需的铁含量。我们以前的工作表明，铁可以直接激活致癌作用 通过一种假定的翻译后修饰，我们称之为铁素化。在这一目标中，我们计划 使用细胞模型和患者衍生的器官模型来探索铁素化的重要性。 实现这些目标将(一)揭示铁积累的机制(二)定义新的铁 相关的脆弱性，以及(Iii)铁如何驱动CRC中的致癌信号。这些研究 还将重点介绍CRC的新途径、遗传脆弱性和药物靶点。

ABSTRACT Colorectal cancer (CRC) can be effectively treated if detected early. However, most tumors are detected at an advanced stage when treatment options are limited. There has been a resurgence in assessing altered cell metabolism in cancer growth. Unlike normal cells, cancer cells rely mainly on aerobic glycolysis for ATP production. Aerobic glycolysis is inefficient in ATP generation, but the glycolytic and TCA cycle intermediates are rerouted for the production of biomass. These studies have led to identification of several critical pathways that have the potential to be therapeutic targets. Currently, much less is known about the contribution of micronutrient metabolism in cancer. Our recent work has established that iron accumulation is critical step in the growth and progression of colon cancer. Colon cancer cells are addicted to high iron levels for cell proliferation. We have clearly shown that there is an accumulation of intra-tumoral iron compared to adjacent normal mucosa. Genetic or dietary restriction of iron leads to a robust decrease in tumor proliferation and progression. However, it is unclear how cancer cells maintain high iron levels, resistant to iron-mediated oxidative toxicity and utilize iron for signaling, survival, and growth. Our goals are to identify mechanism underlying these major gaps to lay the foundation for iron-based therapies in colon cancer. We hypothesize that CRCs bypass the toxicities of high iron accumulation to fuel oncogenic signaling. Cellular iron levels are regulated via a hepatic hormone hepcidin. Hepcidin binds to an iron exporter ferroportin leading to degradation and inhibition of iron export. We show that colon tumor epithelium express high levels of hepcidin and low ferroportin. Aim 1 will delineate if hepcidin/ferroportin axis is the major mechanism leading to iron accumulation and if it can be targeted for therapy. Iron is essential for growth but can be highly toxic to a cell. Iron levels need to be tightly controlled. Iron via the Fenton reaction leads to high superoxide formation and initiates a form of non-apoptotic cell death called ferroptosis. Our recent data suggest that CRCs actively suppress ferroptosis. Aim 2 will understand mechanisms leading to resistance of iron induced damage. In Aim 3 we will address why CRCs need high levels of iron to maintain growth. Our previous work showed that iron can directly activate oncogenic kinases through a putative posttranslational modification we termed ferritinylation. In this Aim we plan to explore the importance of ferritinylation using cell models and patient-derived organoid models. Accomplishing these Aims will (i) uncover mechanisms of iron accumulation (ii) define novel iron related vulnerabilities, and (iii) characterize how iron drives oncogenic signaling in CRC. These studies will also highlight new pathways, genetic vulnerabilities and drug targets for CRC.