Regulation of Lipid Droplets and FOXO3 in Intestinal Epithelial Cell Proliferatio

脂滴和FOXO3对肠上皮细胞增殖的调节

• 批准号: 8628084
• 负责人: Suzana D. Savkovic
• 金额: $ 29.88万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-23 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628084
• 关键词: Adipocytes; Adipose tissue; Cell Cycle; Cell Cycle Arrest; Cell Cycle Progression; Cells; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal; Complex; Data; Developed Countries; Development; Dinoprostone; Disease; Energy-Generating Resources; Epidemic; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Epithelium; Family member; Feedback; Foundations; Genes; Genetic Transcription; Goals; Health; Human; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intestines; Knowledge; Lead; Link; Lipids; Lipomatous neoplasm; Liver; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Mucous Membrane; Mus; Obese Mice; Obesity; Organ; Organelles; Overweight; PTGS2 gene; Patients; Phenotype; Predisposition; Production; Prostaglandins; Recurrence; Regulation; Risk; Role; Signal Pathway; Source; Stimulus; TNF gene; Therapeutic; Tissues; Triglycerides; Tumor Biology; Tumor Suppressor Proteins; Ulcerative Colitis; adenoma; base; cancer cell; inhibitor/antagonist; lipid metabolism; malignant colon tumor; neoplastic; new therapeutic target; receptor; response; theories; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Obesity and overweight, which have been immense epidemics in developed countries for the last two decades, are associated with a wide array of diseases including cancer of different organs such as the colon. To date, the underlying mechanisms for these associations are not completely understood. One of emerging possibilities is that excess lipids accumulated in the tissue of obese individuals directly stimulates progression of colonic tumors. Intracellular lipids are stored in lipid droplets (LDs), dynamic organelles found in adipose tissue, as well as in many human tumors. It is believed that LDs are the source of energy that drives proliferation, a hallmark of tumor progression; however, their regulation and function are not well understood. Our preliminary data reveals that LD accumulation is increased in the colon of obese mice as well as in inflamed and neoplastic colonic tissue. Moreover, LDs are negatively regulated by tumor suppressor FOXO3, while stimulating LDs accumulation leads to a loss of FOXO3 activity. Thus we propose the existence of an LD-FOXO3 network that also includes PI3K and SIRT6 (a negative regulator of triglycerides (TGs). Moreover, preliminary data suggested that the LD-FOXO3 network is critical in proliferation of colonic cancer cells and also operates in obesity influence colonic epithelium. There is support that the LD-FOXO3 network is upstream control by EGFR and/or PGE2, while downstream modifies cell cycle regulators and triglyceride synthesis. The central hypothesis of this proposal is that proliferation in colonic cells controlled by LD-FOXO3 network leads to coordinate LD accumulation and cell cycle progression dependent on loss of FOXO3 is one mechanism responsible for obesity related colon tumor progression. The following Specific Aims are proposed: Aim 1. To assess if the LD induced proliferative response in colonic cancer cells depends on FOXO3 activity via (a) activation of EGFR and whether this is dependent on PGE2, (b) PI3K dependent loss of FOXO3 cell cycle arrest, and (c) SIRT6 dependent, a negative regulator of TGs in colon cancer cells. Aim 2. To determine if TNF-induced proliferation and consequent LD accumulation are due to activation of EGFR, PGE2 and a loss of FOXO3 cell cycle arrest and SIRT6 (in vitro), and (b) to find if selective blockade of LD in TNF treated Foxo3 or EGFR deficient mice suppresses proliferation of colonic epithelia by promoting Foxo3 dependent SIRT6 and cell cycle arrest and TGs. Aim 3. To assess if obesity and a deficiency in Foxo3 (a) exacerbated adenoma progression in DSS/AOM model leading to alterations in regulators of G0-G1 checkpoint and TGs, (b) if adenoma progression is suppressed by selective blockade of LD, PGE2, or TNF, and (c) to identify the Foxo3 dependent genes regulating lipid metabolism. Findings from the proposed study would have significant positive effects on human health by presenting the LD-FOXO3 network as a novel therapeutic target. Although mechanisms of colon cancer progression are complex, the inhibition of LDs may provide an effective blockade to tumor progression in patients with obesity promoted colonic tumor progression.

描述（由申请人提供）：肥胖和超重在过去二十年中在发达国家中非常流行，与多种疾病相关，包括结肠等不同器官的癌症。迄今为止，这些关联的基本机制尚未完全了解。一种新出现的可能性是，肥胖个体组织中积累的过量脂质直接刺激结肠肿瘤的进展。细胞内脂质储存在脂滴 (LD) 中，脂滴是脂肪组织以及许多人类肿瘤中发现的动态细胞器。据认为，LD 是驱动增殖的能量来源，是肿瘤进展的标志；然而，它们的调节和功能尚不清楚。我们的初步数据表明，肥胖小鼠的结肠以及发炎和肿瘤性结肠组织中的 LD 积累增加。此外，LDs受到肿瘤抑制因子FOXO3的负向调节，而刺激LDs积累会导致FOXO3活性丧失。因此，我们提出 LD-FOXO3 网络的存在，其中还包括 PI3K 和 SIRT6（甘油三酯 (TG) 的负调节因子）。此外，初步数据表明 LD-FOXO3 网络对于结肠癌细胞的增殖至关重要，并且在肥胖影响结肠上皮。 有证据表明 LD-FOXO3 网络上游受 EGFR 和/或 PGE2 控制，而下游则修饰细胞周期调节剂和甘油三酯合成。该提议的中心假设是，由 LD-FOXO3 网络控制的结肠细胞增殖导致协调 LD 积累和依赖于 FOXO3 损失的细胞周期进展，这是导致肥胖相关结肠肿瘤进展的一种机制。提出以下具体目标： 目标 1. 通过 (a) EGFR 激活以及这是否依赖于 PGE2，(b) PI3K 依赖性 FOXO3 细胞损失，评估 LD 诱导的结肠癌细胞增殖反应是否依赖于 FOXO3 活性周期停滞，以及 (c) SIRT6 依赖性，结肠癌细胞中 TG 的负调节因子。目标 2. 确定 TNF 诱导的增殖和随后的 LD 积累是否是由于 EGFR、PGE2 的激活以及 FOXO3 细胞周期停滞和 SIRT6 的丧失（体外）所致，以及 (b) 确定 TNF 中是否选择性阻断 LD处理 Foxo3 或 EGFR 缺陷小鼠通过促进 Foxo3 依赖性 SIRT6 和细胞周期停滞和 TG 来抑制结肠上皮细胞的增殖。目标 3. 评估肥胖和 Foxo3 缺陷 (a) 在 DSS/AOM 模型中是否加剧了腺瘤进展，导致 G0-G1 检查点和 TG 调节因子的改变，(b) 选择性阻断 LD 是否可以抑制腺瘤进展， PGE2 或 TNF，以及 (c) 鉴定调节脂质代谢的 Foxo3 依赖性基因。 通过将 LD-FOXO3 网络作为新的治疗靶点，拟议研究的结果将对人类健康产生显着的积极影响。尽管结肠癌进展的机制很复杂，但对于肥胖促进结肠肿瘤进展的患者来说，抑制LDs可能会有效阻断肿瘤进展。

项目成果

The Implications of JK-1(FAM134B) Gene in Human Cancer

JK-1(FAM134B)基因在人类癌症中的意义

• 发表时间: 2024-09-14
• 作者: K. Kasem

Intestinal inflammation requires FOXO3 and prostaglandin E2-dependent lipogenesis and elevated lipid droplets.

肠道炎症需要 FOXO3 和前列腺素 E2 依赖性脂肪生成和升高的脂滴。

• DOI: 10.1152/ajpgi.00407.2015
• 发表时间: 2016-03-11
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: S. Heller;Chloe Cable;Harrison M Penrose;Rania M. Makboul;Debjani Biswas;Maleen Cabe;S. Crawford;S. Savkovic
• 通讯作者: S. Savkovic

Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6.

表皮生长因子受体介导的增殖取决于通过 FOXO3/Sirtuin6 负调节环调节的脂滴密度的增加。

• DOI: 10.1016/j.bbrc.2015.11.119
• 发表时间: 2016-01-15
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Penrose H;Heller S;Cable C;Makboul R;Chadalawada G;Chen Y;Crawford SE;Savkovic SD
• 通讯作者: Savkovic SD